Compositions and methods for treating CNS disorders

ABSTRACT

Provided herein is a compound of Formula (I-I), or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I-I), and methods of using the compounds, e.g. in the treatment of CNS-related disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a U.S. National Phase Application under 35U.S.C. § 371 of International Application PCT/US2019/013315, filed Jan.11, 2019, which claims priority to and the benefit of U.S. ProvisionalApplication No. 62/617,134 filed Jan. 12, 2018, U.S. ProvisionalApplication No. 62/616,768 filed Jan. 12, 2018, and U.S. ProvisionalApplication No. 62/728,514 filed Sep. 7, 2018, the entireties of each ofwhich are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Brain excitability is defined as the level of arousal of an animal, acontinuum that ranges from coma to convulsions, and is regulated byvarious neurotransmitters. In general, neurotransmitters are responsiblefor regulating the conductance of ions across neuronal membranes. Atrest, the neuronal membrane possesses a potential (or membrane voltage)of approximately −70 mV, the cell interior being negative with respectto the cell exterior. The potential (voltage) is the result of ion (K⁺,Na⁺, Cl⁻, organic anions) balance across the neuronal semipermeablemembrane. Neurotransmitters are stored in presynaptic vesicles and arereleased under the influence of neuronal action potentials. Whenreleased into the synaptic cleft, a change of potential occurs from −70mV to −50 mV. This effect is mediated by postsynaptic nicotinicreceptors which are stimulated by acetylcholine to increase membranepermeability to Na⁺ ions. The reduced membrane potential stimulatesneuronal excitability in the form of a postsynaptic action potential.

In the case of the GABA receptor complex (GRC), the effect on brainexcitability is mediated by γ-aminobutyric acid (GABA), aneurotransmitter. GABA has a profound influence on overall brainexcitability because up to 40% of the neurons in the brain utilize GABAas a neurotransmitter. GABA regulates the excitability of individualneurons by regulating the conductance of chloride ions across theneuronal membrane. GABA interacts with its recognition site on the GRCto facilitate the flow of chloride ions down an electrochemical gradientof the GRC into the cell. An intracellular increase in the levels ofthis anion causes hyperpolarization of the transmembrane potential,rendering the neuron less susceptible to excitatory inputs, i.e.,reduced neuron excitability. In other words, the higher the chloride ionconcentration in the neuron, the lower the brain excitability and levelof arousal.

It is well-documented that the GRC is responsible for the mediation ofanxiety, seizure activity, and sedation. Thus, GABA and drugs that actlike GABA or facilitate the effects of GABA (e.g., the therapeuticallyuseful barbiturates and benzodiazepines (BZs), such as Valium®) producetheir therapeutically useful effects by interacting with specificregulatory sites on the GRC. Accumulated evidence has now indicated thatin addition to the benzodiazepine and barbiturate binding site, the GRCcontains a distinct site for neuroactive steroids. See, e.g., Lan, N. C.et al., Neurochem. Res. (1991) 16:347-356.

Neuroactive steroids can occur endogenously. The most potent endogenousneuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and3α-21-dihydroxy-5-reduced pregnan-20-one, metabolites of hormonalsteroids progesterone and deoxycorticosterone, respectively. The abilityof these steroid metabolites to alter brain excitability was recognizedin 1986 (Majewska, M. D. et al., Science 232:1004-1007 (1986); Harrison,N. L. et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)).

New and improved compounds are needed that act as modulating agents forbrain excitability, as well as agents for the prevention and treatmentof CNS-related diseases. The compounds, compositions, and methodsdescribed herein are directed toward this end.

SUMMARY OF THE INVENTION

Provided herein are compounds designed, for example, to act as GABAmodulators. In some embodiments, such compounds are envisioned to beuseful as therapeutic agents for treating a CNS-related disorder.

In an aspect, provided herein is a compound of Formula (I-I)

or a pharmaceutically acceptable salt thereof.

In an aspect, provided herein is a compound of Formula (I-II):

or a pharmaceutically acceptable salt thereof.

In an aspect, provided herein is a compound of Formula (I-III):

or a pharmaceutically acceptable salt thereof.

In an aspect, provided herein is a compound of Formula (I-IV):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (I-Iea) orFormula (I-Iea-1)

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (I-leg) orFormula (I-leg-1),

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (I-Ih) orFormula (I-Ih-1),

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (I-Ii) orFormula (I-Ii-1),

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is selected from the group consistingof the compounds identified in Table I-1 herein.

In some embodiments, provided herein is a compound of Formula (II-I)

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula (II-II)

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula (II-IIa)

or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of Formula (II-III)

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-I) is the compound ofFormula (II-Ia), (II-Iaa), (II-Iab), or (II-Iad)

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-I) is the compound ofFormula (II-ba), (II-Ibb), (II-Ibc), or (II-bd)

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-I) is the compound ofFormula (II-Ica), (II-Icb), (II-Icc), or (II-Icd)

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-I) is the compound isof Formula (II-Iea), (II-Ieb), (II-Iec), or (II-Ied)

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-I) is the compound isof Formula (II-Iega), (II-Iegb), (II-Iegc), or (II-Iegd),

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-I) is the compound isof Formula (II-Iha), (II-Ihb), (II-Ihe), or (II-Ihd),

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-I) is the compound isof Formula (II-Iia), (II-Iib), (II-Iic), or (II-Iid),

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-II) or (II-III) is thecompound is of Formula (II-IIa), (II-IIaa), (II-IIab), (II-IIac),(II-IIad) or (II-IIae)

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-II) or (II-III) is thecompound is of Formula (II-IIna), (II-IInb), (II-IInc), (II-IInd), or(II-IIne)

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-II) or (II-III) is thecompound is of Formula (II-IIma), (II-IImb), (II-IImc), (II-IImd),(II-IIme), (II-IImf), (II-IImg), (II-IImh), (II-IImi), or (II-IImj)

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-II) or (II-III) is thecompound is of Formula (II-IIpa), (II-IIpb), (II-IIpc), (II-IIpd),(II-IIpe), (II-IIpf), (II-IIpg), (II-IIph), (II-IIpi), (II-IIpj) or(II-IIpk)

or a pharmaceutically acceptable salt thereof. or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the compound of Formula (II-II) or (II-III) is thecompound is of Formula (II-IIwa), (II-IIwb), (II-IIwc), (II-IIwd),(II-IIwe), (II-IIwf), (II-IIwg), (II-IIwh), (II-IIwi), (II-IIwj), or(II-IIwk)

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-II) or (II-III) is ofFormula (II-IIega), (II-IIegb), (II-IIegc), (II-IIegd), (II-IIege),(II-IIegf), (II-IIegg), (II-IIegh), (II-IIegi), (II-IIegj), or(II-IIegk)

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is selected from the group consistingof the compounds identified in Table II-1 herein.

TABLE II-1 Example Compound ID Structure II-1 II-A11b

II-2 II-A13b

II-3 II-B12

II-4 II-B14

In one aspect, provided herein is a pharmaceutically acceptable salt ofa compound described herein (e.g., a compound of Formula (I-I), (I-II),(I-III), (I-IV), (II-I), (II-II), or (II-III)).

In one aspect, provided herein is a pharmaceutical compositioncomprising a compound described herein (e.g., a compound of Formula(I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. In certain embodiments, the compound of thepresent invention is provided in an effective amount in thepharmaceutical composition. In certain embodiments, the compound of thepresent invention is provided in a therapeutically effective amount. Incertain embodiments, the compound of the present invention is providedin a prophylactically effective amount.

Compounds of the present invention as described herein, act, in certainembodiments, as GABA modulators, e.g., effecting the GABA_(A) receptorin either a positive or negative manner. As modulators of theexcitability of the central nervous system (CNS), as mediated by theirability to modulate GABA_(A) receptor, such compounds are expected tohave CNS-activity.

Thus, in another aspect, provided are methods of treating a CNS-relateddisorder in a subject in need thereof, comprising administering to thesubject an effective amount of a compound of the present invention. Incertain embodiments, CNS-related disorder is a sleep disorder, a mooddisorder, a schizophrenia spectrum disorder, a convulsive disorder, adisorder of memory and/or cognition, a movement disorder, a personalitydisorder, autism spectrum disorder, pain, traumatic brain injury, avascular disease, a substance abuse disorder and/or withdrawal syndrome,tinnitus, or status epilepticus. In certain embodiments, the CNS-relateddisorder is depression. In certain embodiments, the CNS-related disorderis postpartum depression. In certain embodiments, the CNS-relateddisorder is major depressive disorder. In certain embodiments, the majordepressive disorder is moderate major depressive disorder. In certainembodiments, the major depressive disorder is severe major depressivedisorder. In certain embodiments, the compound is administered orally,subcutaneously, intravenously, or intramuscularly. In certainembodiments, the compound is administered orally. In certainembodiments, the compound is administered chronically. In certainembodiments, the compound is administered continuously, e.g., bycontinuous intravenous infusion.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

As generally described herein, the present invention provides compoundsdesigned, for example, to act as GABA_(A) receptor modulators. Incertain embodiments, such compounds are envisioned to be useful astherapeutic agents for treating a CNS-related disorder (e.g., a disorderas described herein, for example depression, such as post-partumdepression or major depressive disorder).

Definitions Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Isomers, e.g., stereoisomers, can be isolated from mixtures by methodsknown to those skilled in the art, including chiral high pressure liquidchromatography (HPLC) and the formation of chiral salts; or preferredisomers can be prepared by asymmetric syntheses. See, for example,Jacques et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977);Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); andWilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E. L.Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972). Theinvention additionally encompasses compounds described herein asindividual isomers substantially free of other isomers, andalternatively, as mixtures of various isomers.

“Stereoisomers”: It is also to be understood that compounds that havethe same molecular formula but differ in the nature or sequence ofbonding of their atoms or the arrangement of their atoms in space aretermed “isomers.” Isomers that differ in the arrangement of their atomsin space are termed “stereoisomers.” Stereoisomers that are not mirrorimages of one another are termed “diastereomers” and those that arenon-superimposable mirror images of each other are termed “enantiomers.”When a compound has an asymmetric center, for example, it is bonded tofour different groups, a pair of enantiomers is possible. An enantiomercan be characterized by the absolute configuration of its asymmetriccenter and is described by the R- and S-sequencing rules of Cahn andPrelog, or by the manner in which the molecule rotates the plane ofpolarized light and designated as dextrorotatory or levorotatory (i.e.,as (+) or (−)-isomers respectively). A chiral compound can exist aseither individual enantiomer or as a mixture thereof. A mixturecontaining equal proportions of the enantiomers is called a “racemicmixture”.

As used herein a pure enantiomeric compound is substantially free fromother enantiomers or stereoisomers of the compound (i.e., inenantiomeric excess). In other words, an “S” form of the compound issubstantially free from the “R” form of the compound and is, thus, inenantiomeric excess of the “R” form. The term “enantiomerically pure” or“pure enantiomer” denotes that the compound comprises more than 75% byweight, more than 80% by weight, more than 85% by weight, more than 90%by weight, more than 91% by weight, more than 92% by weight, more than93% by weight, more than 94% by weight, more than 95% by weight, morethan 96% by weight, more than 97% by weight, more than 98% by weight,more than 98.5% by weight, more than 99% by weight, more than 99.2% byweight, more than 99.5% by weight, more than 99.6% by weight, more than99.7% by weight, more than 99.8% by weight or more than 99.9% by weight,of the enantiomer. In certain embodiments, the weights are based upontotal weight of all enantiomers or stereoisomers of the compound.

In the compositions provided herein, an enantiomerically pure compoundcan be present with other active or inactive ingredients. For example, apharmaceutical composition comprising enantiomerically pureR-position/center/carbon compound can comprise, for example, about 90%excipient and about 10% enantiomerically pure R-compound. In certainembodiments, the enantiomerically pure R-compound in such compositionscan, for example, comprise, at least about 95% by weight R-compound andat most about 5% by weight S-compound, by total weight of the compound.For example, a pharmaceutical composition comprising enantiomericallypure S-compound can comprise, for example, about 90% excipient and about10% enantiomerically pure S-compound. In certain embodiments, theenantiomerically pure S-compound in such compositions can, for example,comprise, at least about 95% by weight S-compound and at most about 5%by weight R-compound, by total weight of the compound. In certainembodiments, the active ingredient can be formulated with little or noexcipient or carrier.

As used herein, the term “diastereomeric purity” refers to the amount ofa compound having the depicted absolute stereochemistry, expressed as apercentage of the total amount of the depicted compound and itsdiastereomers. The term “diastereomierically pure” denotes that thecompound comprises more than 75% by weight, more than 80% by weight,more than 85% by weight, more than 90% by weight, more than 91% byweight, more than 92% by weight, more than 93% by weight, more than 94%by weight, more than 95% by weight, more than 96% by weight, more than97% by weight, more than 98% by weight, more than 98.5% by weight, morethan 99% by weight, more than 99.2% by weight, more than 99.5% byweight, more than 99.6% by weight, more than 99.7% by weight, more than99.8% by weight or more than 99.9% by weight, of the diastereomer.Methods for determining diastereomeric and enantiomeric purity arewell-known in the art. Diastereomeric purity can be determined by anyanalytical method capable of quantitatively distinguishing between acompound and its diastereomers, such as high performance liquidchromatography (HPLC).

The articles “a” and “an” may be used herein to refer to one or to morethan one (i.e. at least one) of the grammatical objects of the article.By way of example “an analogue” means one analogue or more than oneanalogue.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group having from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). Insome embodiments, an alkyl group has 1 to 12 carbon atoms (“C₁₋₁₂alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms(“C₁₋₁₀ alkyl”). In some embodiments, an alkyl group has 1 to 9 carbonatoms (“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkyl group has 1to 7 carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl grouphas 1 to 6 carbon atoms (“C₁₋₆ alkyl”, also referred to herein as “loweralkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms(“C₁₋₅ alkyl”). In some embodiments, an alkyl group has 1 to 4 carbonatoms (“C₁₋₄ alkyl”). In some embodiments, an alkyl group has 1 to 3carbon atoms (“C₁₋₃ alkyl”). In some embodiments, an alkyl group has 1to 2 carbon atoms (“C₁₋₂ alkyl”). In some embodiments, an alkyl grouphas 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkyl group has2 to 6 carbon atoms (“C₂₋₆ alkyl”). Examples of C₁₋₄ alkyl groupsinclude methyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl(C₄), tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅),3-pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅),tertiary amyl (C₅), and n-hexyl (C₆). Additional examples of alkylgroups include n-heptyl (C₇), n-octyl (C₈) and the like. Unlessotherwise specified, each instance of an alkyl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents;e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1substituent. In certain embodiments, the alkyl group is unsubstitutedC₁₋₁₀ alkyl (e.g., —CH₃). In certain embodiments, the alkyl group issubstituted C₁₋₁₀ alkyl. Common alkyl abbreviations include Me (—CH₃),Et (—CH₂CH₃), iPr (—CH(CH₃)₂), nPr (—CH₂CH₂CH₃), n-Bu (—CH₂CH₂CH₂CH₃),or i-Bu (—CH₂CH(CH₃)₂).

“Alkylene” refers to an alkyl group wherein two hydrogens are removed toprovide a divalent radical, and which may be substituted orunsubstituted. Unsubstituted alkylene groups include, but are notlimited to, methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene(—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—), pentylene (—CH₂CH₂CH₂CH₂CH₂—),hexylene (—CH₂CH₂CH₂CH₂CH₂CH₂—), and the like. Exemplary substitutedalkylene groups, e.g., substituted with one or more alkyl (methyl)groups, include but are not limited to, substituted methylene(—CH(CH₃)—, (—C(CH₃)₂—), substituted ethylene (—CH(CH₃)CH₂—,—CH₂CH(CH₃)—, —C(CH₃)₂CH₂—, —CH₂C(CH₃)₂—), substituted propylene(—CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—, —CH₂CH₂CH(CH₃)—, —C(CH₃)₂CH₂CH₂—,—CH₂C(CH₃)₂CH₂—, —CH₂CH₂C(CH₃)₂—), and the like. When a range or numberof carbons is provided for a particular alkylene group, it is understoodthat the range or number refers to the range or number of carbons in thelinear carbon divalent chain. Alkylene groups may be substituted orunsubstituted with one or more substituents as described herein.

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon doublebonds), and optionally one or more carbon-carbon triple bonds (e.g., 1,2, 3, or 4 carbon-carbon triple bonds) (“C₂₋₂₀ alkenyl”). In certainembodiments, alkenyl does not contain any triple bonds. In someembodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl.In certain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triplebonds), and optionally one or more carbon-carbon double bonds (e.g., 1,2, 3, or 4 carbon-carbon double bonds) (“C₂₋₂₀ alkynyl”). In certainembodiments, alkynyl does not contain any double bonds. In someembodiments, an alkynyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄alkynyl groups include, without limitation, ethynyl (C₂), 1-propynyl(C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkynylgroups as well as pentynyl (C₅), hexynyl (C₆), and the like. Additionalexamples of alkynyl include heptynyl (C₇), octynyl (C₈), and the like.Unless otherwise specified, each instance of an alkynyl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) withone or more substituents; e.g., for instance from 1 to 5 substituents, 1to 3 substituents, or 1 substituent. In certain embodiments, the alkynylgroup is unsubstituted C₂₋₁₀ alkynyl. In certain embodiments, thealkynyl group is substituted C₂₋₁₀ alkynyl.

The term “heteroalkyl,” as used herein, refers to an alkyl group, asdefined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4)heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus)within the parent chain, wherein the one or more heteroatoms is insertedbetween adjacent carbon atoms within the parent carbon chain and/or oneor more heteroatoms is inserted between a carbon atom and the parentmolecule, i.e., between the point of attachment. In certain embodiments,a heteroalkyl group refers to a saturated group having from 1 to 10carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₁₀ alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 9carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₉ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 8carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₈ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 7carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₇ alkyl”). In someembodiments, a heteroalkyl group is a group having 1 to 6 carbon atomsand 1, 2, or 3 heteroatoms (“heteroC₁₋₆ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1or 2 heteroatoms (“heteroC₁₋₅ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms (“heteroC₁₋₄ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1heteroatom (“heteroC₁₋₃ alkyl”). In some embodiments, a heteroalkylgroup is a saturated group having 1 to 2 carbon atoms and 1 heteroatom(“heteroC₁₋₂ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 carbon atom and 1 heteroatom (“heteroC₁alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC₂₋₆ alkyl”).Unless otherwise specified, each instance of a heteroalkyl group isindependently unsubstituted (an “unsubstituted heteroalkyl”) orsubstituted (a “substituted heteroalkyl”) with one or more substituents.In certain embodiments, the heteroalkyl group is an unsubstitutedheteroC₁₋₁₀ alkyl. In certain embodiments, the heteroalkyl group is asubstituted heteroC₁₋₁₀ alkyl.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 πelectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Typicalaryl groups include, but are not limited to, groups derived fromaceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, andtrinaphthalene. Particularly aryl groups include phenyl, naphthyl,indenyl, and tetrahydronaphthyl. Unless otherwise specified, eachinstance of an aryl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted aryl”) or substituted (a “substitutedaryl”) with one or more substituents. In certain embodiments, the arylgroup is unsubstituted C₆₋₁₄ aryl. In certain embodiments, the arylgroup is substituted C₆₋₁₄ aryl.

In certain embodiments, an aryl group substituted with one or more ofgroups selected from halo, C₁-C₈ alkyl, C₁-C₈ haloalkyl, cyano, hydroxy,C₁-C₈ alkoxy, and amino.

Examples of representative substituted aryls include the following

wherein one of R⁵⁶ and R⁵⁷ may be hydrogen and at least one of R⁵⁶ andR⁵⁷ is each independently selected from C₁-C₈ alkyl, C₁-C₈ haloalkyl,4-10 membered heterocyclyl, alkanoyl, C₁-C₈ alkoxy, heteroaryloxy,alkylamino, arylamino, heteroarylamino, NR⁵⁸COR⁵⁹, —NR⁵⁸SOR⁵⁹NR⁵⁸SO₂R⁵⁹, COOalkyl, COOaryl, CONR⁵⁸R⁵⁹, CONR⁵⁸OR⁵⁹, NR⁵⁸R⁵⁹,SO₂NR⁵⁸R⁵⁹, S-alkyl, SOalkyl, SO₂alkyl, Saryl, SOaryl, SO₂aryl; or R⁵⁶and R⁵⁷ may be joined to form a cyclic ring (saturated or unsaturated)from 5 to 8 atoms, optionally containing one or more heteroatomsselected from the group N, O, or S. R⁶⁰ and R⁶¹ are independentlyhydrogen, C₁-C₈ alkyl, C₁-C₄haloalkyl, C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, substituted C₆-C₁₀ aryl, 5-10 memberedheteroaryl, or substituted 5-10 membered heteroaryl.

“Fused aryl” refers to an aryl having two of its ring carbon in commonwith a second aryl or heteroaryl ring or with a carbocyclyl orheterocyclyl ring.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system.

Bicyclic heteroaryl groups wherein one ring does not contain aheteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) thepoint of attachment can be on either ring, i.e., either the ring bearinga heteroatom (e.g., 2-indolyl) or the ring that does not contain aheteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of representative heteroaryls include the following:

wherein each Z is selected from carbonyl, N, NR⁶⁵, O, and S; and R⁶⁵ isindependently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, and 5-10 membered heteroaryl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C₃₈carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ringcarbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, a carbocyclylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In someembodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C₅₋₁₀carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include, withoutlimitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl (C₄),cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl(C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. ExemplaryC₃₋₈ carbocyclyl groups include, without limitation, the aforementionedC₃₋₄ carbocyclyl groups as well as cycloheptyl (C₇), cycloheptenyl (C₇),cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈),cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl(C₈), and the like. Exemplary C₃₋₁₀ carbocyclyl groups include, withoutlimitation, the aforementioned C₃₋₈ carbocyclyl groups as well ascyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl(C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀),spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclyl ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is a substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₃₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged or spiro ring systemsuch as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingtwo heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Nitrogen-containing heterocyclyl” group means a 4- to 7-memberednon-aromatic cyclic group containing at least one nitrogen atom, forexample, but without limitation, morpholine, piperidine (e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline,imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methyl piperazine. Particular examples includeazetidine, piperidone and piperazone.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g.heteroaryl, cycloalkenyl, e.g. cycloheteroalkenyl, and the like havingfrom 1 to 5, and particularly from 1 to 3 heteroatoms.

“Acyl” refers to a radical —C(O)R²⁰, where R²⁰ is hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl, asdefined herein. “Alkanoyl” is an acyl group wherein R²⁰ is a group otherthan hydrogen. Representative acyl groups include, but are not limitedto, formyl (—CHO), acetyl (—C(═O)CH₃), cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl (—C(═O)Ph), benzylcarbonyl(—C(═O)CH₂Ph), C(O)—C₁-C₈ alkyl, —C(O)—(CH₂)_(t)(C₆-C₁₀ aryl),—C(O)—(CH₂)_(t)(5-10 membered heteroaryl), —C(O)—(CH₂)_(t)(C₃-C₁cycloalkyl), and —C(O)—(CH₂)_(t)(4-10 membered heterocyclyl), wherein tis an integer from 0 to 4. In certain embodiments, R²¹ is C₁-C₈ alkyl,substituted with halo or hydroxy; or C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, arylalkyl, 5-10 membered heteroaryl orheteroarylalkyl, each of which is substituted with unsubstituted C₁-C₄alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy.

“Alkoxy” refers to the group —OR²⁹ where R²⁹ is substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl. Particular alkoxygroups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6carbon atoms. Further particular alkoxy groups have between 1 and 4carbon atoms.

In certain embodiments, R²⁹ is a group that has 1 or more substituents,for instance from 1 to 5 substituents, and particularly from 1 to 3substituents, in particular 1 substituent, selected from the groupconsisting of amino, substituted amino, C₆-C₁₀ aryl, aryloxy, carboxyl,cyano, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—. Exemplary‘substituted alkoxy’ groups include, but are not limited to,—O—(CH₂)_(t)(C₆-C₁₀ aryl), —O—(CH₂)_(t)(5-10 membered heteroaryl),—O—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and —O—(CH₂)_(t)(4-10 memberedheterocyclyl), wherein t is an integer from 0 to 4 and any aryl,heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves besubstituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy. Particular exemplary‘substituted alkoxy’ groups are —OCF₃, —OCH₂CF₃, —OCH₂Ph,—OCH₂-cyclopropyl, —OCH₂CH₂OH, and —OCH₂CH₂NMe₂.

“Amino” refers to the radical —NH₂.

“Oxo group” refers to —C(═O)—.

“Substituted amino” refers to an amino group of the formula —N(R³⁸)₂wherein R³⁸ is hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or an amino protecting group, wherein at leastone of R³⁸ is not a hydrogen. In certain embodiments, each R³⁸ isindependently selected from hydrogen, C₁-C₈ alkyl, C₃-C₈ alkenyl, C₃-C₈alkynyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl, 4-10 memberedheterocyclyl, or C₃-C₁₀ cycloalkyl; or C₁-C₈ alkyl, substituted withhalo or hydroxy; C₃-C₈ alkenyl, substituted with halo or hydroxy; C₃-C₈alkynyl, substituted with halo or hydroxy, or —(CH₂)_(t)(C₆-C₁₀ aryl),—(CH₂)_(t)(5-10 membered heteroaryl), —(CH₂)_(t)(C₃-C₁₀ cycloalkyl), or—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integer between0 and 8, each of which is substituted by unsubstituted C₁-C₄ alkyl,halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy; or both R³⁸ groups are joined to form an alkylene group.

Exemplary “substituted amino” groups include, but are not limited to,—NR³⁹—C₁-C₈ alkyl, —NR³⁹—(CH₂)_(t)(C₆-C₁₀ aryl), —NR³⁹—(CH₂)_(t)(5-10membered heteroaryl), —NR³⁹—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and—NR³⁹—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integerfrom 0 to 4, for instance 1 or 2, each R³⁹ independently represents H orC₁-C₈ alkyl; and any alkyl groups present, may themselves be substitutedby halo, substituted or unsubstituted amino, or hydroxy; and any aryl,heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselvesbe substituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy. For the avoidance of doubtthe term ‘substituted amino’ includes the groups alkylamino, substitutedalkylamino, alkylarylamino, substituted alkylarylamino, arylamino,substituted arylamino, dialkylamino, and substituted dialkylamino asdefined below. Substituted amino encompasses both monosubstituted aminoand disubstituted amino groups.

“Carboxy” refers to the radical —C(O)OH.

“Cyano” refers to the radical —CN.

“Halo” or “halogen” refers to fluoro (F), chloro (C₁), bromo (Br), andiodo (I). In certain embodiments, the halo group is either fluoro orchloro.

“Haloalkyl” refers to an alkyl radical in which the alkyl group issubstituted with one or more halogens. Typical haloalkyl groups include,but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl,chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl,tetrafluoroethyl, and the like.

“Hydroxy” refers to the radical —OH.

“Nitro” refers to the radical —NO₂.

“Thioketo” refers to the group ═S.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that results in theformation of a stable compound. The present invention contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this invention, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —N^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR—, —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa),—P(═O)(R^(aa))₂—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂,—P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups; or two geminalhydrogens on a carbon atom are replaced with the group ═O, ═S,═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc); each instance of R^(aa)is, independently, selected from C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(aa) groups arejoined to form a 3-14 membered heterocyclyl or 5-14 membered heteroarylring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, or two R^(bb) groups are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ haloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(cc) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 Rd groups;each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR)OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ee)C(═NR^(ff))N(R^(ff))₂,—NR^(ee)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee),—P(═O)(R^(ee))₂—OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups, or twogeminal R^(dd) substituents can be joined to form ═O or ═S;each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R¹groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R¹ groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions(e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonicacid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate,ethanoate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, and the like).

These and other exemplary substituents are described in more detail inthe Detailed Description, and Claims. The invention is not intended tobe limited in any manner by the above exemplary listing of substituents.

Other Definitions

As used herein, the term “modulation” refers to the inhibition orpotentiation of GABA_(A) receptor function. A “modulator” (e.g., amodulator compound) may be, for example, an agonist, partial agonist,antagonist, or partial antagonist of the GABA_(A) receptor.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or a state government or thecorresponding agency in countries other than the United States, or thatis listed in the U.S. Pharmacopoeia or other generally recognizedpharmacopoeia for use in animals, and more particularly, in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts are non-toxic may be inorganic or organic acid addition saltsand base addition salts. Specifically, such salts include: (1) acidaddition salts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non-toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like. The term“pharmaceutically acceptable cation” refers to an acceptable cationiccounter-ion of an acidic functional group. Such cations are exemplifiedby sodium, potassium, calcium, magnesium, ammonium, tetraalkylammoniumcations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977)66(1): 1-79.

The term “prodrug” is intended to encompass therapeutically inactivecompounds that, under physiological conditions, are converted into thetherapeutically active agents of the present invention. One method formaking a prodrug is to design selected moieties that are hydrolyzed orcleaved at a targeted in vivo site of action under physiologicalconditions to reveal the desired molecule which then produces itstherapeutic effect. In certain embodiments, the prodrug is converted byan enzymatic activity of the subject.

In an alternate embodiment, the present invention provides prodrugs ofcompound of Formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or(II-III), wherein the prodrug includes a cleavable moiety on the C₃hydroxy as depicted in Formula (I-I), (I-II), (I-III), (I-IV), (II-I),(II-II), or (II-III).

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons.

Thus, two structures may be in equilibrium through the movement of 7electrons and an atom (usually H). For example, enols and ketones aretautomers because they are rapidly interconverted by treatment witheither acid or base. Another example of tautomerism is the aci- andnitro-forms of phenylnitromethane, that are likewise formed by treatmentwith acid or base. Tautomeric forms may be relevant to the attainment ofthe optimal chemical reactivity and biological activity of a compound ofinterest.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or anon-human animal, e.g., a mammal such as primates (e.g., cynomolgusmonkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents,cats, and/or dogs. In certain embodiments, the subject is a human. Incertain embodiments, the subject is a non-human animal.

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to as a hydroxyl protectinggroup). Oxygen protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃, —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂ and —P(═O)(NR)₂, wherein R^(aa),R^(bb), and R^(cc) are as defined herein. Oxygen protecting groups arewell known in the art and include those described in detail inProtecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts,3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn),triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS),t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), andtosylate (Ts).

In certain embodiments, the substituent present on a sulfur atom is asulfur protecting group (also referred to as a thiol protecting group).Sulfur protecting groups include, but are not limited to, —R^(aa),—N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa), —C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂,—S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃, —P(R^(cc))₂, —P(R^(cc))₃,—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, and—P(═O)R^(bb))₂ wherein R^(aa), R^(bb), and R^(cc) are as defined herein.Sulfur protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

In certain embodiments, the substituent present on a nitrogen atom is anamino protecting group (also referred to herein as a nitrogen protectinggroup). Amino protecting groups include, but are not limited to, —OH,—OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)OR^(aa), —C(═O)N(R^(cc))₂,—S(═O)₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14-memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14-membered heteroaryl groups, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdgroups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are as definedherein. Amino protecting groups are well known in the art and includethose described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,incorporated herein by reference.

Exemplary amino protecting groups include, but are not limited to amidegroups (e.g., —C(═O)R^(aa)), which include, but are not limited to,formamide and acetamide; carbamate groups (e.g., —C(═O)OR^(aa)), whichinclude, but are not limited to, 9-fluorenylmethyl carbamate (Fmoc),t-butyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups(e.g., —S(═O)₂R^(aa)), which include, but are not limited to,p-toluenesulfonamide (Ts), methanesulfonamide (Ms), andN-[2-(trimethylsilyl)ethoxy]methylamine (SEM).

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition.In an alternate embodiment, the present invention contemplatesadministration of the compounds of the present invention as aprophylactic before a subject begins to suffer from the specifieddisease, disorder or condition.

In general, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response, e.g., to treat aCNS-related disorder, is sufficient to induce anesthesia or sedation. Aswill be appreciated by those of ordinary skill in this art, theeffective amount of a compound of the invention may vary depending onsuch factors as the desired biological endpoint, the pharmacokinetics ofthe compound, the disease being treated, the mode of administration, andthe age, weight, health, and condition of the subject. An effectiveamount encompasses therapeutic and prophylactic treatment.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment of a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. A therapeutically effective amountof a compound means an amount of therapeutic agent, alone or incombination with other therapies, which provides a therapeutic benefitin the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease orcondition, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease, disorder or condition, or one or more symptoms associated withthe disease, disorder or condition, or prevent its recurrence.

A prophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the disease,disorder or condition. The term “prophylactically effective amount” canencompass an amount that improves overall prophylaxis or enhances theprophylactic efficacy of another prophylactic agent.

Compounds

It should be appreciated that formulas described herein may referenceparticular carbon atoms, such as C17, C3, C19, etc. These references arebased on the position of carbon atoms according to steroid nomenclatureknown and used in the industry, as shown below:

For example, C17 refers to the carbon at position 17 and C3 refers tothe carbon at position 3.

In an aspect, provided herein is a compound of Formula (I-I):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2;X is —O—, —N(R^(X))—, or —S(O)_(y)—, wherein R^(X) is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, —S(O)₂(R^(A0)), —C(O)(R^(A0)), orsubstituted or unsubstituted heteroaryl, wherein each instance of R^(A0)is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, and y is 0, 1, or 2; R^(3a) ishydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R¹⁹ is hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted C₂-C₆ alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl; R⁵ is hydrogen or methyl;R¹ is substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, —OC(═O)R^(A1),—OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A1))₂, —SC(═O)R^(A2),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —NHC(═O)R^(A1),—NHC(═O)OR^(A1), —NHC(═O)SR^(A1), —NHC(═O)N(R^(A1))₂, —OS(═O)₂R^(A2),—OS(═O)₂OR^(A1), —S—S(═O)₂R^(A2), —S—S(═O)₂OR^(A1), —S(═O)R^(A2),—SO₂R^(A2), or —S(═O)₂OR^(A1), wherein each instance of R^(A1) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached to anoxygen atom, a sulfur protecting group when attached to a sulfur atom, anitrogen protecting group when attached to a nitrogen atom, or twoR^(A1) groups are joined to form an substituted or unsubstitutedheterocyclic or heteroaryl ring; and R^(A2) is substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; each of R^(15a),R^(15b), R^(16a), and R^(16b) is each independently hydrogen, halogen,cyano, hydroxyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, —CN(R^(A1))₂, —C(O)R^(A1),—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A1))₂,—SC(═O)R^(A2), —SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂,—NHC(═O)R^(A1), —NHC(═O)OR^(A1), —NHC(═O)SR^(A1), —NHC(═O)N(R^(A1))₂,—OS(═O)₂R^(A2), —OS(═O)₂OR^(A1), —S(═O)₂R^(A2), —S—S(═O)₂OR^(A1),—S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), wherein each instance ofR^(A1) is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, an oxygen protecting group whenattached to an oxygen atom, a sulfur protecting group when attached to asulfur atom, a nitrogen protecting group when attached to a nitrogenatom, —SO₂R^(A2), —C(O)R^(A2), or two R^(A1) groups are joined to forman substituted or unsubstituted heterocyclic or heteroaryl ring; andR^(A2) is substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; or R^(15a) and R^(15b) or R^(16a) and R^(16b) are joined toform an oxo (═O) group; and each of R^(1a), R^(1b), R^(2a), R^(2b),R^(4a), R^(4b), R^(7a), R^(7b), R^(11a), R^(11b), R^(12a), and R^(12b)is independently hydrogen, halogen, cyano, hydroxyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted heterocyclyl, or substituted or unsubstituted alkynyl,—OR^(D1), —OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1),wherein each instance of R^(D1) is independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl, anoxygen protecting group when attached to an oxygen atom, a nitrogenprotecting group when attached to a nitrogen atom, or two R^(D1) groupsare joined to form an substituted or unsubstituted heterocyclic ring; orany one of R^(2a) and R^(2b), R^(4a) and R^(4b), R^(7a) and R^(7b),R^(11a) and R^(11b), and R^(12a) and R^(12b) are joined to form an oxo(═O) group, wherein when m is 0, then R¹ is substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, —OC(═O)R^(A1),—OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A1))₂, —SC(═O)R^(A2),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —NHC(═O)R^(A1),—NHC(═O)OR^(A1), —NHC(═O)SR^(A1), —NHC(═O)N(R^(A1))₂, —OS(═O)₂R^(A2),—OS(═O)₂OR^(A1), —S—S(═O)₂R^(A2), —S—S(═O)₂OR^(A1), —S(═O)R^(A2),—SO₂R^(A2), or —S(═O)₂OR^(A1), wherein each instance of R^(A1) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached to anoxygen atom, a sulfur protecting group when attached to a sulfur atom, anitrogen protecting group when attached to a nitrogen atom, or twoR^(A1) groups are joined to form an substituted or unsubstitutedheterocyclic or heteroaryl ring; and R^(A2) is substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In an aspect, provided herein is a compound of Formula (I-II):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2; Xis —O—, —N(R^(X))—, or —S(O)_(y)—, wherein R^(X) is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, —S(O)₂(R^(A0)), —C(O)(R^(A0)), orsubstituted or unsubstituted heteroaryl, wherein each instance of R^(A0)is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, and y is 0, 1, or 2; R^(3a) ishydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R¹⁹ is hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted C₂-C₆ alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl; R⁵ is hydrogen or methyl;each of R^(6a) and R^(6b) is independently hydrogen, halogen, cyano,hydroxyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, or substituted or unsubstituted alkynyl, orR^(6a) and R^(6b) are joined to form an oxo (═O) group; R¹ issubstituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, —OC(═O)R^(A1),—OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A1))₂, —SC(═O)R^(A2),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —NHC(═O)R^(A1),—NHC(═O)OR^(A1), —NHC(═O)SR^(A1), —NHC(═O)N(R^(A1))₂, —OS(═O)₂R^(A2),—OS(═O)₂OR^(A1), —S—S(═O)₂R^(A2), —S—S(═O)₂OR^(A1), —S(═O)R^(A2),—SO₂R^(A2), or —S(═O)₂OR^(A1), wherein each instance of R^(A1) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached to anoxygen atom, a sulfur protecting group when attached to a sulfur atom, anitrogen protecting group when attached to a nitrogen atom, or twoR^(A1) groups are joined to form an substituted or unsubstitutedheterocyclic or heteroaryl ring; and R^(A2) is substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl; each of R^(15a),R^(15b), R^(16a) and R^(16b) is each independently hydrogen, halogen,cyano, hydroxyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR^(A1), —SR^(A1), —N(R^(A1))₂, —CN(R^(A1))₂, —C(O)R^(A1),—OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1), —OC(═O)N(R^(A1))₂,—SC(═O)R^(A2), —SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂,—NHC(═O)R^(A1), —NHC(═O)OR^(A1), —NHC(═O)SR^(A1), —NHC(═O)N(R^(A1))₂,—OS(═O)₂R^(A2), —OS(═O)₂OR^(A1), —S—S(═O)₂R^(A2), —S—S(═O)₂OR^(A1),—S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), wherein each instance ofR^(A1) is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, an oxygen protecting group whenattached to an oxygen atom, a sulfur protecting group when attached to asulfur atom, a nitrogen protecting group when attached to a nitrogenatom, —SO₂R^(A1), —C(O)R^(A2), or two R^(A1) groups are joined to forman substituted or unsubstituted heterocyclic or heteroaryl ring; andR^(A2) is substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; or R^(15a) and R^(15b) or R^(16a) and R^(16b) are joined toform an oxo (═O) group; and each of R^(1a), R^(1b), R^(2a), R^(2b),R^(4a), R^(4b), R^(11a), R^(11b), R^(12a), and R^(12b) is independentlyhydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted alkynyl, —OR^(D1),—OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein eachinstance of R^(D1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl, an oxygen protectinggroup when attached to an oxygen atom, a nitrogen protecting group whenattached to a nitrogen atom, or two R^(D1) groups are joined to form ansubstituted or unsubstituted heterocyclic ring; or any one of R^(2a) andR^(2b), R^(4a) and R^(4b), R^(11a) and R^(11b), and R^(12a) and R^(12b)are joined to form an oxo (═O) group, when m is 0, then R¹ issubstituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —OR^(A1), —SR^(A1),—N(R^(A1))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A1))₂, —SC(═O)R^(A2), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A1))₂, —NHC(═O)R^(A1), —NHC(═O)OR^(A1), —NHC(═O)SR^(A1),—NHC(═O)N(R^(A1))₂, —OS(═O)₂R^(A2), —OS(═O)₂OR^(A1), —S—S(═O)₂R^(A2),—S—S(═O)₂OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), whereineach instance of R^(A1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, an oxygen protectinggroup when attached to an oxygen atom, a sulfur protecting group whenattached to a sulfur atom, a nitrogen protecting group when attached toa nitrogen atom, or two R^(A1) groups are joined to form an substitutedor unsubstituted heterocyclic or heteroaryl ring; and R^(A2) issubstituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In an aspect, provided herein is a compound of Formula (I-III):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2; Xis —O—, —N(R^(X))—, or —S(O)_(y)—, wherein R^(X) is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, —S(O)₂(R^(A0)), —C(O)(R^(A0)), orsubstituted or unsubstituted heteroaryl, wherein each instance of R^(A0)is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, and y is 0, 1, or 2; R^(3a) ishydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁵ is hydrogen or methyl; R¹ is substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(A1), —SR^(A1),—N(R^(A1))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A1))₂, —SC(═O)R^(A2), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A1))₂, —NHC(═O)R^(A1), —NHC(═O)OR^(A1), —NHC(═O)SR^(A1),—NHC(═O)N(R^(A1))₂, —OS(═O)₂R^(A2), —OS(═O)₂OR^(A1), —S(═O)₂R^(A2),—S—S(═O)₂OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), whereineach instance of R^(A1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, an oxygen protectinggroup when attached to an oxygen atom, a sulfur protecting group whenattached to a sulfur atom, a nitrogen protecting group when attached toa nitrogen atom, or two R^(A1) groups are joined to form an substitutedor unsubstituted heterocyclic or heteroaryl ring; and R^(A2) issubstituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; each of R^(15a), R^(15b), R^(16a), and R^(16b) is eachindependently hydrogen, halogen, cyano, hydroxyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(A1), —SR^(A1),—N(R^(A1))₂, —CN(R^(A1))₂, —C(O)R^(A1), —OC(═O)R^(A1), —OC(═O)OR^(A1),—OC(═O)SR^(A1), —OC(═O)N(R^(A1))₂, —SC(═O)R^(A2), —SC(═O)OR^(A1),—SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —NHC(═O)R^(A1), —NHC(═O)OR^(A1),—NHC(═O)SR^(A1), —NHC(═O)N(R^(A1))₂, —OS(═O)₂R^(A2), —OS(═O)₂OR^(A1),—S(═O)₂R^(A2), —S—S(═O)₂OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or—S(═O)₂OR^(A1), wherein each instance of R^(A1) is independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, an oxygen protecting group when attached to an oxygen atom,a sulfur protecting group when attached to a sulfur atom, a nitrogenprotecting group when attached to a nitrogen atom, —SO₂R^(A2),—C(O)R^(A2), or two R^(A1) groups are joined to form an substituted orunsubstituted heterocyclic or heteroaryl ring; and R^(A2) is substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; orR^(15a) and R^(15b) or R^(16a) and R^(16b) are joined to form an oxo(═O) group; and each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b),R^(7a), R^(7b), R^(11a), R^(11b), R^(12a), and R^(12b) is independentlyhydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted alkynyl, —OR^(D1),—OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein eachinstance of R^(D1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl, an oxygen protectinggroup when attached to an oxygen atom, a nitrogen protecting group whenattached to a nitrogen atom, or two R^(D1) groups are joined to form ansubstituted or unsubstituted heterocyclic ring; or any one of R^(2a) andR^(2b), R^(4a) and R^(4b), R^(7a) and R^(7b), R^(11a) and R^(12b), andR^(12a) and R^(12b) are joined to form an oxo (═O) group.

In an aspect, provided herein is a compound of Formula (I-IV):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2;X is —O—, —N(R^(X))—, or —S(O)_(y)—, wherein R^(X) is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, —S(O)₂(R^(A0)), —C(O)(R^(A0)), orsubstituted or unsubstituted heteroaryl, wherein each instance of R^(A0)is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, and y is 0, 1, or 2; R^(3a) ishydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R⁵ is hydrogen or methyl; each of R^(6a) and R^(6b) isindependently hydrogen, halogen, cyano, hydroxyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, orsubstituted or unsubstituted alkynyl, or R^(6a) and R^(6b) are joined toform an oxo (═O) group; R¹ is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —OR^(A1), —SR^(A1),—N(R^(A1))₂, —OC(═O)R^(A1), —OC(═O)OR^(A1), —OC(═O)SR^(A1),—OC(═O)N(R^(A1))₂, —SC(═O)R^(A2), —SC(═O)OR^(A1), —SC(═O)SR^(A1),—SC(═O)N(R^(A1))₂, —NHC(═O)R^(A1), —NHC(═O)OR^(A1), —NHC(═O)SR^(A1),—NHC(═O)N(R^(A1))₂, —OS(═O)₂R^(A2), —OS(═O)₂OR^(A1), —S—S(═O)₂R^(A2),—S—S(═O)₂OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or —S(═O)₂OR^(A1), whereineach instance of R^(A1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, an oxygen protectinggroup when attached to an oxygen atom, a sulfur protecting group whenattached to a sulfur atom, a nitrogen protecting group when attached toa nitrogen atom, or two R^(A1) groups are joined to form an substitutedor unsubstituted heterocyclic or heteroaryl ring; and R^(A2) issubstituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; each of R^(15a), R^(15b), R^(16a), and R^(16b) is eachindependently hydrogen, halogen, cyano, hydroxyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(A1), —SR^(A1),—N(R^(A1))₂, —CN(R^(A1))₂, —C(O)R^(A1), —OC(═O)R^(A1), —OC(═O)OR^(A1),—OC(═O)SR^(A1), —OC(═O)N(R^(A1))₂, —SC(═O)R^(A2), —SC(═O)OR^(A1),—SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —NHC(═O)R^(A1), —NHC(═O)OR^(A1),—NHC(═O)SR^(A1), —NHC(═O)N(R^(A1))₂, —OS(═O)₂R^(A2), —OS(═O)₂OR^(A1),—S(═O)₂R^(A2), —S—S(═O)₂OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or—S(═O)₂OR^(A1), wherein each instance of R^(A1) is independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, an oxygen protecting group when attached to an oxygen atom,a sulfur protecting group when attached to a sulfur atom, a nitrogenprotecting group when attached to a nitrogen atom, —SO₂R^(A2),—C(O)R^(A2), or two R^(A1) groups are joined to form an substituted orunsubstituted heterocyclic or heteroaryl ring; and R^(A2) is substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; orR^(15a) and R^(15b) or R^(16a) and R^(16b) are joined to form an oxo(═O) group; and each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b),R^(11a), R^(11b), R^(12a), and R^(12b) is independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted alkynyl, —OR^(D1),—OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein eachinstance of R^(D1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl, an oxygen protectinggroup when attached to an oxygen atom, a nitrogen protecting group whenattached to a nitrogen atom, or two R^(D1) groups are joined to form ansubstituted or unsubstituted heterocyclic ring; or any one of R^(2a) andR^(2b), R^(4a) and R^(4b), R^(11a) and R^(11b), and R^(12a) and R^(12b)are joined to form an oxo (═O) group.Formula (I-I), (I-II), (I-III) and (I-IV): Integer m

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 1 or 2.

Formula (I-I), (I-II), (I-III) and (I-IV): X

In some embodiments, X is —O—, —N(R^(X))—, or —S(O)_(y)—, wherein R^(X)may be hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, —S(O)₂(R^(A0)), —C(O)(R^(A0)), orsubstituted or unsubstituted heteroaryl, wherein each instance of R^(A0)is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, and y is 0, 1, or 2.

In some embodiments, X is O.

In some embodiments, X is —N(R^(X))—, and R^(X) is hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, —S(O)₂(R^(A0)), —C(O)(R^(A0)), or substituted orunsubstituted heteroaryl.

In some embodiments, X is —N(R^(X))—, and R^(X) is hydrogen orsubstituted or unsubstituted alkyl.

In some embodiments, X is —S(O)_(y)—, and y is 0, 1, or 2. In someembodiments, X is —S(O)_(y)—, and y is 0. In some embodiments, X is—S(O)_(y)—, and y is 1. In some embodiments, X is —S(O)_(y)—, and y is2.

Formula (I-I), (I-II), (I-III) and (I-IV): Groups R^(1a) and R^(1b)

In some aspects, R^(1a) and R^(1b) are each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted alkynyl, —OR^(D1),—OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein eachinstance of R^(D1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some aspects, R^(1a) and R^(1b) are each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, —OR^(D1), —OC(═O)R^(D1), —NH₂, or—N(R^(D1))₂, wherein each instance of R^(D1) is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some aspects, R^(1a) and R^(1b) is each independently hydrogen,substituted or unsubstituted alkyl, —OR^(D1), —OC(═O)R^(D1), —NH₂,—N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein each instance of R^(D1) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some aspects, R^(1a) and R^(1b) are both hydrogen.

In some embodiments, R^(1a) and R^(1b) is each independently hydrogen orsubstituted or unsubstituted alkyl.

In some embodiments, R^(1a) and R^(1b) is independently hydrogen, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxyhalo, or —OH.

In some embodiments, R^(1a) and R^(1b) is —CH₃, —CH₂CH₃, —OH, —OCH₃, or—CH(CH₃)₂.

Formula (I-I), (I-II), (I-III) and (I-IV): Groups R^(2a) and R^(2b)

In some aspects, R^(2a) and R^(2b) are each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted alkynyl, —OR^(D1),—OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein eachinstance of R^(D1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some aspects, R^(2a) and R^(2b) are each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, —OR^(D1), —OC(═O)R^(D1), —NH₂, or—N(R^(D1))₂, wherein each instance of R^(D1) is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some aspects, R^(2a) and R^(2b) is each independently hydrogen,substituted or unsubstituted alkyl, —OR^(D1), —OC(═O)R^(D1), —NH₂,—N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein each instance of R^(D1) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some aspects, R^(2a) and R^(2b) are both hydrogen.

In some embodiments, R^(2a) and R^(2b) is each independently hydrogen orsubstituted or unsubstituted alkyl.

In some embodiments, R^(2a) and R^(2b) is independently hydrogen, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxyhalo, or —OH.

In some embodiments, R^(2a) and R^(2b) is —CH₃, —CH₂CH₃, —OH, —OCH₃, or—CH(CH₃)₂.

Formula (I-I), (I-II), (I-III) and (I-IV): Groups R^(4a) and R^(4b)

In some aspects, R^(4a) and R^(4b) is each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted alkynyl, —OR^(D1),—OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein eachinstance of R^(D1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some aspects, R^(4a) and R^(4b) is each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, —OR^(D1) OC(═O)R^(D1), —NH₂, or—N(R^(D1))₂, wherein each instance of R^(D1) is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some aspects, R^(4a) and R^(4b) is each independently hydrogen,substituted or unsubstituted alkyl, —OR^(D1), —OC(═O)R^(D1), —NH₂,—N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein each instance of R^(D1) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some aspects, R^(4a) and R^(4b) are both hydrogen. In furtherembodiments, R^(16a) and R^(16b) is each independently hydrogen orsubstituted or unsubstituted alkyl.

In some aspects, R^(4a) and R^(4b) is independently hydrogen, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxyhalo, or —OH. In someother aspects, R^(4a) and R^(4b) is —CH₃, —CH₂CH₃, —OH, —OCH₃, or—CH(CH₃)₂.

Formula (I-I), (I-II), (I-III) and (I-IV): Groups R^(11a) and R^(11b)

In some embodiments, R^(1a) and R^(11b) is each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted alkynyl, —OR^(D1),—OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein eachinstance of R^(D1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some further embodiments, R^(11a) and R^(11b) is each independentlyhydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, —OR^(D1), —OC(═O)R^(D1), —NH₂, or—N(R^(D1))₂, wherein each instance of R^(D1) is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some aspects, R^(11a) and R^(1b) is each independently hydrogen,substituted or unsubstituted alkyl, —OR^(D1), —OC(═O)R^(D1), —NH₂,—N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein each instance of R^(D1) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In some aspects, R^(11a) and R are both hydrogen.

In some aspects, R^(11a) and R^(11b) is each independently hydrogen orsubstituted or unsubstituted alkyl. In some aspects, R^(11a) and R^(11b)is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ alkoxyhalo, or —OH.

In some aspects, R^(11a) and R^(11b) is —CH₃, —CH₂CH₃, —OH, —OCH₃, or—CH(CH₃)₂.

In some embodiments, R^(11a) and R^(11b) are joined together to form oxo(═O).

Formula (I-I), (I-II), (I-III) and (I-IV): Groups R¹⁵ and R^(15b)

In some aspects, R^(15a) and R^(15b) is each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted alkynyl, —OR^(D1),—OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein eachinstance of R^(D1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some embodiments, R^(15a) and R^(15b) is each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, —OR^(D1), —OC(═O)R^(D1), —NH₂, or—N(R^(D1))₂, wherein each instance of R^(D1) is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, R^(15a) and R^(15b) is each independently hydrogen,substituted or unsubstituted alkyl, —OR^(D1), —OC(═O)R^(D1), —NH₂,—N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein each instance of R^(D1) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some further embodiments, R^(15a) and R^(15b) are both hydrogen.

In some aspects, R^(15a) and R^(15b) is each independently hydrogen orsubstituted or unsubstituted alkyl. In some aspects, R^(15a) and R^(15b)is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ alkoxyhalo, or —OH. In some aspects, R^(15a) and R^(15b) is —CH₃,—CH₂CH₃, —OH, —OCH₃, or —CH(CH₃)₂.

Formula (I-I), (I-II), (I-III) and (I-IV): Groups R^(16a) and R^(16b)

In some aspects, R^(16a) and R^(16b) is each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted alkynyl, —OR^(D1),—OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein eachinstance of R^(D1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some embodiments, R^(16a) and R^(16b) is each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, —OR^(D1), —OC(═O)R^(D1), —NH₂, or—N(R^(D1))₂, wherein each instance of R^(D1) is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, R^(16a) and R^(16b) is each independently hydrogen,substituted or unsubstituted alkyl, —OR^(D1), —OC(═O)R^(D1), —NH₂,—N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein each instance of R^(D1) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some further embodiments, R^(16a) and R^(16b) are both hydrogen.

In some aspects, R^(16a) and R^(16b) is each independently hydrogen orsubstituted or unsubstituted alkyl. In some aspects, R^(16a) and R^(16b)is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ alkoxyhalo, or —OH. In some aspects, R^(16a) and R^(16b) is —CH₃,—CH₂CH₃, —OH, —OCH₃, or —CH(CH₃)₂.

Formula (I-I) and (I-III): Groups R^(7a) and R^(7b)

In some embodiments, R^(7a) and R^(7b) is each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted alkynyl, —OR^(D1),—OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein eachinstance of R^(D1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl, or any of R^(7a) andR^(7b) are joined together to form oxo (═O).

In some further embodiments, R^(7a) and R^(7b) is each independentlyhydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, —OR^(D1), —OC(═O)R^(D1), —NH₂, or—N(R^(D1))₂, wherein each instance of R^(D1) is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some aspects, R^(7a) and R^(7b) is each independently hydrogen,substituted or unsubstituted alkyl, —OR^(D1), —OC(═O)R^(D1), —NH₂,—N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein each 15 instance of R^(D1)is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

In some aspects, R^(7a) and R^(7b) are all hydrogen.

In some aspects, R^(7a) and R^(7b) is each independently hydrogen orsubstituted or unsubstituted alkyl. In some aspects, R^(7a) and R^(7b)is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ alkoxyhalo, or —OH.

In some aspects, R^(7a) and R^(7b) is —CH₃, —CH₂CH₃, —OH, —OCH₃, or—CH(CH₃)₂.

In some embodiments, any of R^(7a) and R^(7b) are joined together toform oxo (═O).

Formula (I-I), (I-II), (I-III) and (I-IV): Group R⁵

In some aspects, R⁵ is hydrogen in the cis position, relative to the C19position. In some other aspects, R⁵ is hydrogen in the trans positionrelative to the C19 position. In some embodiments, R⁵ is methyl in thecis position relative to the C19 position. In some further embodiments,R⁵ is methyl in the trans position relative to the C19 position.

Formula (I-I), (I-II), (I-III) and (I-IV): Group R³

In some embodiments, R^(3a) is hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, or substituted orunsubstituted alkynyl.

In some embodiments, R^(3a) is substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some embodiments, R^(3a) is substituted or unsubstituted alkyl.

In some embodiments, R^(3a) is hydrogen. In some embodiments, R^(3a) issubstituted alkyl (e.g., —CH₂OMe or —CH₂OEt, etc.). In some embodiments,R^(3a) is unsubstituted alkyl. In some embodiments, R^(3a) is methyl.

Formula (I-I) and (I-II): Group R⁹

In some aspects, R¹⁹ is C₁-C₆ alkyl. In some aspects, R¹⁹ is C₁-C₆ alkylwith a deuterium substitution.

In some embodiments, R¹⁹ is substituted C₁-C₆ alkyl. In someembodiments, R¹⁹ is unsubstituted C₂-C₆ alkyl.

In some embodiments, R¹⁹ is substituted C₂-C₆ alkenyl. In someembodiments, R¹⁹ is unsubstituted C₂-C₆ alkenyl.

In some embodiments, R¹⁹ is substituted C₂-C₆ alkynyl. In someembodiments, R¹⁹ is unsubstituted C₂-C₆ alkynyl.

In some aspects, R¹⁹ is ethyl.

In some embodiments R¹ is hydrogen.

Formula (I-II) and (I-IV): Group R^(6a) and R^(6b)

In some embodiments, R^(6a) and R^(6b) is independently hydrogen,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, or substituted or unsubstituted alkynyl.

In some aspects, R^(6a) and R^(6b) is independently hydrogen orsubstituted or unsubstituted alkyl.

In some aspects, R^(6a) and R^(6b) is independently hydrogen orsubstituted alkyl. In some embodiments, R^(6a) and R^(6b) isindependently hydrogen or unsubstituted alkyl.

In some aspects, both R^(6a) and R^(6b) are hydrogen. In some aspects,R^(6a) is halo or alkyl and R^(6b) is hydrogen. In some embodiments,R^(6a) and R^(6b) are both halo.

In some aspects, R^(6a) and R^(6b) are both alkyl.

In some embodiments, R^(6a) and R^(6b) are joined to form an oxo group.

Formula (I-I), (I-II), (I-III) and (I-IV): Group R^(12a) and R^(12b)

In some embodiments, R^(12a) and R^(12b) is each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted alkynyl, —OR^(D1),—OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein eachinstance of R^(D1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some aspects, R^(12a) and R^(12b) is each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, —OR^(D1), —OC(═O)R^(D1), —NH₂, or—N(R^(D1))₂, wherein each instance of R^(D1) is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, R^(12a) and R^(12b) is each independently hydrogen,substituted or unsubstituted alkyl, —OR^(D1), —OC(═O)R^(D1), —NH₂,—N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein each instance of R^(D1) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some embodiments, R^(12a) and R^(12b) are both hydrogen.

In some further embodiments, R^(12a) and R^(12b) is each independentlyhydrogen or substituted or unsubstituted alkyl.

In some embodiments, R^(12a) and R^(12b) are joined together to form anoxo group (═O).

In some embodiments, n is 1. In some other embodiments, n is 2.

Formula (I-I), (I-II), (I-III) and (I-IV): Group R¹

In some embodiments, R¹ is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl.

In some embodiments, R¹ is

wherein each instance of R₂₀ is, independently, halogen, —NO₂, —CN,—OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA), —OC(═O)R^(GA),—OC(═O)OR^(GA), —C(═O)N(R^(GA))₂, —N(R^(GA))C(═O)R^(GA),—OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA), —S(═O)₂R^(GA),—S(═O)₂OR^(GA), —OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂, or—N(R^(GA))S(═O)₂R^(GA); substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₃₋₄ carbocylyl, substitutedor unsubstituted 3- to 4-membered heterocyclyl, or optionally two R^(GA)are taken with the intervening atoms to form a substituted orunsubstituted 3- to 4-membered carbocyclic or heterocyclic ring; whereineach instance of R^(GA) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocylyl, substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, or twoR^(GA) groups are taken with the intervening atoms to form a substitutedor unsubstituted carbocyclic or heterocyclic ring; and e is 0, 1, 2, 3,4, or 5 and n is 0, 1, 2, 3, 4, or 5.

In some embodiments, R¹ is

wherein each instance of R₂₀ is, independently, halogen, —NO₂, —CN,—OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA), —OC(═O)R^(GA),—OC(═O)OR^(GA), —C(═O)N(R^(GA))₂, —N(R^(GA))C(═O)R^(GA),—OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA), —S(═O)₂R^(GA),—S(═O)₂OR^(GA), —OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂, or—N(R^(GA))S(═O)₂R^(GA); substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₃₋₄ carbocylyl, substitutedor unsubstituted 3- to 4-membered heterocyclyl, or optionally two R^(GA)are taken with the intervening atoms to form a substituted orunsubstituted 3- to 4-membered carbocyclic or heterocyclic ring; whereineach instance of R^(GA) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocylyl, substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, or twoR^(GA) groups are taken with the intervening atoms to form a substitutedor unsubstituted carbocyclic or heterocyclic ring; and e is 0, 1, 2, or3 and n is 0, 1, 2, 3, or 4.

In some embodiments, the compound is a compound of Formula (I-Iea) orFormula (I-Iea-1)

wherein m is 0, 1, 2 or 3; p is 0, 1, 2, or 3; each R₃₂ is independentlyhalogen, alkyl, hydroxyl, or cyano; or a pharmaceutically acceptablesalt thereof.

In some embodiments, the compound is a compound of Formula (I-leg) orFormula (I-leg-1),

wherein u is 0, 1, or 2; each Z is independently —C(R^(N))—,—C(R^(N))₂—, —O—, —S—, —N—, or N(R^(N))— wherein R^(N) is independentlyhydrogen, substituted or unsubstituted C₁₋₆ alkyl, C(═O)R^(GA),—C(═O)OR^(GA), —C(═O)N(R^(GA))₂, —S(═O)₂R^(GA), or —S(═O)₂N(R^(GA))₂;and each instance of R^(GA) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocylyl, substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, nitrogen protecting group when attached to nitrogen, or twoR^(GA) groups are taken with the intervening atoms to form a substitutedor unsubstituted heterocyclyl or heteroaryl ring; or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the compound is a compound of Formula (I-Ih) orFormula (I-Ih-1),

wherein each R₃₅ is independently halogen, alkyl, hydroxyl, or cyano;and r is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula (I-Ii) orFormula (I-Ii-1)

wherein s is 0, 1, or 2; each T is independently —C(R^(N))—,—C(R^(N))₂—, —O—, —S—, —N—, or N(R^(N)) wherein R^(N) is independentlyhydrogen, substituted or unsubstituted C1-6 alkyl, C(═O)R^(GA),—C(═O)OR^(GA), —C(═O)N(R^(GA))₂, —S(═O)₂R^(GA), or —S(═O)₂N(R^(GA))₂;and each instance of R^(GA) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocylyl, substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, nitrogen protecting group when attached to nitrogen, or twoR^(GA) groups are taken with the intervening atoms to form a substitutedor unsubstituted heterocyclyl or heteroaryl ring; or a pharmaceuticallyacceptable salt thereof.

In some embodiments, provided herein is a compound of Formula (II-I)

or a pharmaceutically acceptable salt thereof, wherein:n is 0, 1 or 2;each X_(c) is independently —C(R^(15a))(R^(15b))—, —O—, —N(R^(B1))—,—S—, —S(O)— or —S(O)₂—, wherein R^(B1) is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, wherein one X_(c) is —O—,—N(R^(A1))—, —S—, —S(O)— or —S(O)₂—; each of R^(15a) and R^(15b) is eachindependently hydrogen, halogen, cyano, hydroxyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(A1), —SR^(A1),—N(R^(A1))₂, —N(R^(A1)), —CN(R^(A1))₂, —C(O)R^(A1), —OC(═O)R^(A1),—OC(═O)OR^(A1), —OC(═O)SR^(A1) OC(═O)N(R^(A1))₂, —SC(═O)R^(A2),—SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂, —NHC(═O)R^(A1),—NHC(═O)OR^(A1), —NHC(═O)SR^(A1), —NHC(═O)N(R^(A1))₂, —OS(═O)₂R^(A2),—OS(═O)₂OR^(A1), —S—S(═O)₂R^(A2), —S—S(═O)₂OR^(A1), —S(═O)R^(A2),—SO₂R^(A2), or —S(═O)₂OR^(A1), wherein each instance of R^(A1) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached to anoxygen atom, a sulfur protecting group when attached to a sulfur atom, anitrogen protecting group when attached to a nitrogen atom, —SO₂R^(A1),—C(O)R^(A2), or two R^(A1) groups are joined to form an substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclic orheteroaryl ring; and R^(A2) is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; or R^(15a) and R^(15b) arejoined to form an oxo (═O) group;R^(3a) is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl;R¹⁹ is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl;R⁵ is hydrogen or methyl, or when

is a double bond, R⁵ is absent;

-   -   each of R^(6a) and R^(6b) is independently hydrogen, halogen,        cyano, hydroxyl, substituted or unsubstituted alkyl, substituted        or unsubstituted alkenyl, or substituted or unsubstituted        alkynyl, or R^(6a) and R^(6b) are joined to form an oxo (═O)        group;    -   R¹ is substituted or unsubstituted alkyl, substituted or        unsubstituted alkenyl, substituted or unsubstituted alkynyl,        substituted or unsubstituted carbocyclyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, —OR^(A1), —SR^(A1),        —N(R^(A1))₂, —N(R^(A1)), —OC(═O)R^(A1), —OC(═O)OR^(A1),        —OC(═O)SR^(A1), —OC(═O)N(R^(A1))₂, —SC(═O)R^(A2),        —SC(═O)OR^(A1), —SC(═O)SR^(A1), —SC(═O)N(R^(A1))₂,        —NHC(═O)R^(A1), —NHC(═O)OR^(A1), —NHC(═O)SR^(A1),        —NHC(═O)N(R^(A1))₂, —OS(═O)₂R^(A2), —OS(═O)₂OR^(A1),        —S—S(═O)₂R^(A2), —S—S(═O)₂OR^(A1), —S(═O)R^(A2), —SO₂R^(A2), or        —S(═O)₂OR^(A1), wherein each instance of R^(A1) is independently        hydrogen, substituted or unsubstituted alkyl, substituted or        unsubstituted alkenyl, substituted or unsubstituted alkynyl,        substituted or unsubstituted carbocyclyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, an oxygen protecting        group when attached to an oxygen atom, a sulfur protecting group        when attached to a sulfur atom, a nitrogen protecting group when        attached to a nitrogen atom, or two R^(A1) groups are joined to        form an substituted or unsubstituted carbocyclyl, substituted or        unsubstituted heterocyclic or heteroaryl ring; and R^(A2) is        substituted or unsubstituted alkyl, substituted or unsubstituted        alkenyl, substituted or unsubstituted alkynyl, substituted or        unsubstituted carbocyclyl, substituted or unsubstituted        heterocyclyl, substituted or unsubstituted aryl, or substituted        or unsubstituted heteroaryl;        each of R^(1a), R^(1b), R^(2a), R^(2b), R^(4a), R^(4b), R^(7a),        R^(7b), R^(11a), R^(11b), R^(12a), or R^(12b), is independently        hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted        alkyl, substituted or unsubstituted alkenyl, substituted or        unsubstituted heterocyclyl, or substituted or unsubstituted        alkynyl, —OR^(D1), —OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or        —NR^(D1)C(═O)R^(D1), wherein each instance of R^(D1) is        independently hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,        substituted or unsubstituted heterocyclyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl,        an oxygen protecting group when attached to an oxygen atom, a        nitrogen protecting group when attached to a nitrogen atom, or        two R^(D1) groups are joined to form an substituted or        unsubstituted heterocyclic ring; or any one of R^(2a) and        R^(2b), R^(4a) and R^(4b), R^(7a) and R^(7b), R^(11a) and        R^(11b), and R^(12a) and R^(12b) are joined to form an oxo (═O)        group; and        wherein        represents a single or double bond, provided if a double bond is        present in        Ring B, then one of R^(6a) or R^(6b) is absent.

In some embodiments, provided herein is a compound of Formula (II-II)

or a pharmaceutically acceptable salt thereof, wherein variables n, R⁵,R¹⁹, R¹, R^(1a), R^(1b), R^(2a), R^(3a), R^(2b), R^(4a), R^(4b), R^(6a),R^(6b), R^(7a), R^(7b), R^(11a), R^(11b), R^(12a), R^(12b), R^(15a) andR^(15b) are defined as in Formula II-I; andeach X_(a) is independently —C(R^(15a))(R^(15b))—, —O—, —N(R^(A1))—,—N—, —S—, —S(O)— or —S(O)₂—, wherein R^(A1) is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, wherein at least oneX_(a) is —O—, —N(R^(A1))—, —S—, —S(O)— or —S(O)₂—; wherein when at leastone X_(a) is —O—, R^(3a) is hydrogen, R¹⁹ is methyl, and R^(7a) orR^(7b) is hydroxyl, then R^(15a) and R^(15b) do not form oxo.

In some embodiments, provided herein is a compound of Formula (II-IIa)

or a pharmaceutically acceptable salt thereof;wherein variables n R⁵, R¹⁹, R¹, R^(1b), R^(2a), R^(2b), R^(4a), R^(4b),R^(6a), R^(6b), R^(7a), R^(7b), R^(11a), R^(11b), R^(12a), R^(12b),R^(15a) and R^(15b) are defined as in Formula II-I; andeach X_(a) is independently —C(R^(15a))(R^(15b))—, —O—, —N(R^(A1))—,—N—, —S—, —S(O)— or —S(O)₂—, wherein R^(A1) is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, wherein at least oneX_(a) is —O—, —N(R^(A1))—, —S—, —S(O)— or —S(O)₂—; and

R^(3a) is substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some embodiments, provided herein is a compound of Formula (II-III)

or a pharmaceutically acceptable salt thereof;wherein variables n R⁵, R¹⁹, R¹, R^(1a), R^(1b), R^(2a), R^(2b), R^(3a),R^(4a), R^(4b), R^(6a), R^(6b), R^(7a), R^(7b), R^(11a), R^(11b),R^(12a), R^(12b), R^(15a) and R^(15b), are defined as in Formula II-I;andeach X_(b) and X_(b1) is independently —C(R^(15a))(R^(15b))—, —O—, —N—,—N(R^(A1))—, —S—, —S(O)— or —S(O)₂—, wherein R^(A1) is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, wherein at least one X_(b) or X_(b1) is —O—, —N(R^(A1))—,—S—, —S(O)— or —S(O)₂—.Formula (II-I), (II-II), or (II-III): X_(a), X_(b), X_(b1), or X_(c),

In some embodiments, each X_(c) is independently —C(R^(15a))(R^(15b))—,—O—, —N(R^(B1))—, —S—, —S(O)— or —S(O)₂—, wherein R^(B1) is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, wherein one X_(c) is —O—, —N(R^(A1))—, —S—, —S(O)— or—S(O)₂—.

In some embodiments, each X_(a) is independently —C(R^(15a))(R^(15b))—,—O—, —N(R^(A1))—, —N—, —S—, —S(O)— or —S(O)₂—, wherein R^(A1) ishydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, wherein at least one X_(a) is —O—, —N(R^(A1))—, —S—, —S(O)—or —S(O)₂—; wherein when at least one X_(a) is —O—, R^(3a) is hydrogen,R¹⁹ is methyl, and R^(7a) or R^(7b) is hydroxyl, then R^(15a) andR^(15b) do not form oxo.

In some embodiments, each X_(b) and X_(b1) is independently—C(R^(15a))(R^(15b))—, —O—, —N—, —N(R^(A1))—, —S—, —S(O)— or —S(O)₂—,wherein R^(A1) is hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, wherein at least one X_(b) orX_(b1) is —O—, —N(R^(A1))—, —S—, —S(O)— or —S(O)₂—.

In some embodiments, when X_(b) is —O— and R¹⁹ is methyl, then R^(3a) issubstituted or unsubstituted alkyl.

In some embodiments, X_(c) is —O—, —N(H)—, —N(CH₃)—, or —N(CH₂CH₃)—.

In some embodiments, X_(b) or X_(b1) is —O—, —N(H)—, —N(CH₃)—, or—N(CH₂CH₃)—.

In some embodiments, X_(a) is —O—, —N(H)—, —N(CH₃)—, —N(CH₂CH₃)—, or—S(O)₂—.

In some embodiments, X_(c) is —O—.

Formula (II-I), (II-II), and (II-III): Groups R^(1a) and R^(1b)

In some aspects, R^(1a) and R^(1b) are each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted alkynyl, —OR^(D1),—OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein eachinstance of R^(D1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some aspects, R^(1a) and R^(1b) are each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, —OR^(D1) OC(═O)R^(D1), —NH₂, or—N(R^(D1))₂, wherein each instance of R^(D1) is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some aspects, R^(1a) and R^(1b) is each independently hydrogen,substituted or unsubstituted alkyl, —OR^(D1), —OC(═O)R^(D1), —NH₂,—N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein each instance of R^(D1) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some aspects, R^(1a) and R^(1b) are both hydrogen.

In some embodiments, R^(1a) and R^(1b) is each independently hydrogen orsubstituted or unsubstituted alkyl.

In some embodiments, R^(1a) and R^(1b) is independently hydrogen, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxyhalo, or —OH.

In some embodiments, R^(1a) and R^(1b) is —CH₃, —CH₂CH₃, —OH, —OCH₃, or—CH(CH₃)₂.

Formula (II-I), (II-II), and (II-III): Groups R^(2a) and R^(2b)

In some aspects, R^(2a) and R^(2b) are each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted alkynyl, —OR^(D1),—OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein eachinstance of R^(D1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some aspects, R^(2a) and R^(2b) are each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, —OR^(D1), —OC(═O)R^(D1), —NH₂, or—N(R^(D1))₂, wherein each instance of R^(D1) is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some aspects, R^(2a) and R^(2b) is each independently hydrogen,substituted or unsubstituted alkyl, —OR^(D1), —OC(═O)R^(D1), —NH₂,—N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein each instance of R^(D1) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some aspects, R^(2a) and R^(2b) are both hydrogen.

In some embodiments, R^(2a) and R^(2b) is each independently hydrogen orsubstituted or unsubstituted alkyl.

In some embodiments, R^(2a) and R^(2b) is independently hydrogen, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxyhalo, or —OH.

In some embodiments, R^(2a) and R^(2b) is —CH₃, —CH₂CH₃, —OH, —OCH₃, or—CH(CH₃)₂.

Formula (II-I), (II-II), and (II-III): Groups R^(4a) and R^(4b)

In some aspects, R^(4a) and R^(4b) is each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted alkynyl, —OR^(D1),—OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein eachinstance of R^(D1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some aspects, R^(4a) and R^(4b) is each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, —OR^(D1), —OC(═O)R^(D1), —NH₂, or—N(R^(D1))₂, wherein each instance of R^(D1) is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some aspects, R^(4a) and R^(4b) is each independently hydrogen,substituted or unsubstituted alkyl, —OR^(D1), —OC(═O)R^(D1), —NH₂,—N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein each instance of R^(D1) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some aspects, R^(4a) and R^(4b) are both hydrogen. In furtherembodiments, R^(16a) and R^(16b) is each independently hydrogen orsubstituted or unsubstituted alkyl.

In some aspects, R^(4a) and R^(4b) is independently hydrogen, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxyhalo, or —OH. In someother aspects, R^(4a) and R^(4b) is —CH₃, —CH₂CH₃, —OH, —OCH₃, or—CH(CH₃)₂.

Formula (II-I), (II-II), and (II-III): Groups R^(11a) and R^(11b)

In some embodiments, R^(11a) and R^(11b) is each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted alkynyl, —OR^(D1),—OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein eachinstance of R^(D1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some further embodiments, R^(11a) and R^(11b) is each independentlyhydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, —OR^(D1), —OC(═O)R^(D1), —NH₂, or—N(R^(D1))₂, wherein each instance of R^(D1) is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some aspects, R^(11a) and R^(11b) is each independently hydrogen,substituted or unsubstituted alkyl, —OR^(D1), —OC(═O)R^(D1), —NH₂,—N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein each instance of R^(D1) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In some aspects, R^(11a) and R are both hydrogen.

In some aspects, R^(11a) and R^(11b) is each independently hydrogen orsubstituted or unsubstituted alkyl. In some aspects, R^(11a) and R^(11b)is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ alkoxyhalo, or —OH.

In some aspects, R^(11a) and R^(11b) is —CH₃, —CH₂CH₃, —OH, —OCH₃, or—CH(CH₃)₂.

In some embodiments, R^(11a) and R^(11b) are joined together to form oxo(═O).

Formula (II-I), (II-II), and (II-III): Groups R^(15a) and R^(15b)

In some aspects, R^(15a) and R^(15b) is each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted alkynyl, —OR^(D1),—OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein eachinstance of R^(D1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some embodiments, R^(15a) and R^(15b) is each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, —OR^(D1), —OC(═O)R^(D1), —NH₂, or—N(R^(D1))₂, wherein each instance of R^(D1) is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, R^(15a) and R^(15b) is each independently hydrogen,substituted or unsubstituted alkyl, —OR^(D1), —OC(═O)R^(D1), —NH₂,—N(RD)₂, or —NR^(D1)C(═O)R^(D1), wherein each instance of R^(D1) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some further embodiments, R^(15a) and R^(15b) are both hydrogen.

In some aspects, R^(15a) and R^(15b) is each independently hydrogen orsubstituted or unsubstituted alkyl. In some aspects, R^(15a) and R^(15b)is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ alkoxyhalo, or —OH. In some aspects, R^(15a) and R^(15b) is —CH₃,—CH₂CH₃, —OH, —OCH₃, or —CH(CH₃)₂.

Formula (II-I), (II-II), and (II-III): Groups R^(7a) and R^(7b)

In some embodiments, R^(7a) and R^(7b) is each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted alkynyl, —OR^(D1),—OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein eachinstance of R^(D1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl, or any of R^(7a) andR^(7b) are joined together to form oxo (═O).

In some further embodiments, R^(7a) and R^(7b) is each independentlyhydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, —OR^(D1), —OC(═O)R^(D1), —NH₂, or—N(R^(D1))₂, wherein each instance of R^(D1) is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some aspects, R^(7a) and R^(7b) is each independently hydrogen,substituted or unsubstituted alkyl, —OR^(D1), —OC(═O)R^(D1), —NH₂,—N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein each instance of R^(D1) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some aspects, R^(7a) and R^(7b) are all hydrogen.

In some aspects, R^(7a) and R^(7b) is each independently hydrogen orsubstituted or unsubstituted alkyl. In some aspects, R^(7a) and R^(7b)is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ alkoxyhalo, or —OH.

In some aspects, R^(7a) and R^(7b) is —CH₃, —CH₂CH₃, —OH, —OCH₃, or—CH(CH₃)₂.

In some embodiments, any of R^(7a) and R^(7b) are joined together toform oxo (═O).

Formula (II-I), (II-II), and (II-III): Group R⁵

In some aspects, R⁵ is hydrogen in the cis position, relative to the C19position. In some other aspects, R⁵ is hydrogen in the trans positionrelative to the C19 position. In some embodiments, R⁵ is methyl in thecis position relative to the C19 position. In some further embodiments,R⁵ is methyl in the trans position relative to the C19 position.

Formula (II-I), (II-II), and (II-III): Group R³,

In some embodiments, R^(3a) is hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, or substituted orunsubstituted alkynyl.

In some embodiments, R^(3a) is substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some embodiments, R^(3a) is substituted or unsubstituted alkyl.

In some embodiments, R^(3a) is hydrogen. In some embodiments, R^(3a) issubstituted alkyl (e.g., —CH₂OMe or —CH₂OEt, etc.). In some embodiments,R^(3a) is unsubstituted alkyl. In some embodiments, R^(3a) is methyl.

Formula (II-I), (II-II), and (II-III): Group R⁹

In some embodiments, R¹⁹ is hydrogen.

In some aspects, R¹⁹ is C₁-C₆ alkyl. In some aspects, R¹⁹ is C₁-C₆ alkylwith a deuterium substitution.

In some embodiments, R¹⁹ is substituted C₁-C₆ alkyl. In someembodiments, R¹⁹ is unsubstituted C₁-C₆ alkyl.

In some embodiments, R¹⁹ is substituted C₂-C₆ alkenyl. In someembodiments, R¹⁹ is unsubstituted C₂-C₆ alkenyl.

In some embodiments, R¹⁹ is substituted C₂-C₆ alkynyl. In someembodiments, R¹⁹ is unsubstituted C₂-C₆ alkynyl.

In some embodiments, R¹⁹ is methyl (e.g., —CH₃).

In some aspects, R¹⁹ is ethyl.

Formula (II-I), (II-II), and (II-III): Group R^(6a) and R^(6b)

In some embodiments, R^(6a) and R^(6b) is independently hydrogen,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, or substituted or unsubstituted alkynyl.

In some aspects, R^(6a) and R^(6b) is independently hydrogen orsubstituted or unsubstituted alkyl.

In some aspects, R^(6a) and R^(6b) is independently hydrogen orsubstituted alkyl. In some embodiments, R^(6a) and R^(6b) isindependently hydrogen or unsubstituted alkyl.

In some aspects, both R^(6a) and R^(6b) are hydrogen. In some aspects,R^(6a) is halo or alkyl and R^(6b) is hydrogen. In some embodiments,R^(6a) and R^(6b) are both halo.

In some aspects, R^(6a) and R^(6b) are both alkyl.

In some embodiments, R^(6a) and R^(6b) are joined to form an oxo group.

Formula (II-I), (II-II), and (II-III): Group R^(12a) and R^(b)

In some embodiments, R^(12a) and R^(12b) is each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, or substituted or unsubstituted alkynyl, —OR^(D1),—OC(═O)R^(D1), —NH₂, —N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein eachinstance of R^(D1) is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl.

In some aspects, R^(12a) and R^(12b) is each independently hydrogen,halogen, cyano, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, —OR^(D1), —OC(═O)R^(D1), —NH₂, or—N(R^(D1))₂, wherein each instance of R^(D1) is independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In some embodiments, R^(12a) and R^(12b) is each independently hydrogen,substituted or unsubstituted alkyl, —OR^(D1), —OC(═O)R^(D1), —NH₂,—N(R^(D1))₂, or —NR^(D1)C(═O)R^(D1), wherein each instance of R^(D1) isindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.

In some embodiments, R^(12a) and R^(12b) are both hydrogen.

In some further embodiments, R^(12a) and R^(12b) is each independentlyhydrogen or substituted or unsubstituted alkyl.

In some embodiments, R^(12a) and R^(12b) are joined together to form anoxo group (═O).

Formula (II-I), (II-II), and (II-III): Integer n

In some embodiments, n is 1. In some other embodiments, n is 2.

Formula (II-I), (II-II), and (II-III): Group R¹

In some embodiments, R¹ is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl.

In some embodiments, R¹ is

wherein each instance of R₂₀ is, independently, halogen, —N₂, —CN,—OR^(GA), —NN(R^(GA))₂—C(═O)R^(GA), —C(═O)OR^(GA), —OC(═O)R^(GA),—OC(═O)OR^(GA), —C(═O)N(R^(GA))₂, —N(R^(GA))C(═O)R^(GA),—OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA), —S(═O)₂R^(GA), S(═O)₂OR^(GA),—OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂, or —N(R^(GA))S(═O)₂R^(GA);substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₄ carbocylyl, substituted or unsubstituted 3- to4-membered heterocyclyl, or optionally two R^(GA) are taken with theintervening atoms to form a substituted or unsubstituted 3- to4-membered carbocyclic or heterocyclic ring; wherein each instance ofR^(GA) is independently hydrogen, substituted or unsubstitutedC₁₋₆alkyl, substituted or unsubstituted C₂₋₆alkenyl, substituted orunsubstituted C₂₋₆alkynyl, substituted or unsubstituted C₃₋₆carbocylyl,substituted or unsubstituted 3- to 6-membered heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, anoxygen protecting group when attached to oxygen, a nitrogen protectinggroup when attached to nitrogen, or two R^(GA) groups are taken with theintervening atoms to form a substituted or unsubstituted carbocyclic orheterocyclic ring; and e is 0, 1, 2, 3, 4, or 5 and n is 0, 1, 2, 3, 4,or 5.In some embodiments, wherein R¹ is

wherein each instance of R₂₀ is, independently, halogen, —NO₂, —CN,—OR^(GA), —N(R^(GA))₂, —C(═O)R^(GA), —C(═O)OR^(GA), —OC(═O)R^(GA),—OC(═O)OR^(GA), —C(═O)N(R^(GA))₂, —N(R^(GA))C(═O)R^(GA),—OC(═O)N(R^(GA))₂, —N(R^(GA))C(═O)OR^(GA), —S(═O)₂R^(GA),—S(═O)₂OR^(GA), —OS(═O)₂R^(GA), —S(═O)₂N(R^(GA))₂, or—N(R^(GA))S(═O)₂R^(GA); substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₃₋₄ carbocylyl, substitutedor unsubstituted 3- to 4-membered heterocyclyl, or optionally two R^(GA)are taken with the intervening atoms to form a substituted orunsubstituted 3- to 4-membered carbocyclic or heterocyclic ring; whereineach instance of R^(GA) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocylyl, substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, a nitrogen protecting group when attached to nitrogen, or twoR^(GA) groups are taken with the intervening atoms to form a substitutedor unsubstituted carbocyclic or heterocyclic ring; and e is 0, 1, 2, 3,or 4.In some embodiments, the compound of Formula (II-I) is of Formula(II-Ia), (II-Iaa), (II-lab), or (II-lad)

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-I) is of Formula(II-Iba), (II-Ibb), (II-Ibc), or (II-Ibd)

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-I) is of Formula(II-Ica), (II-Icb), 10 (II-Icc), or (II-Icd)

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-I) is of Formula(II-Iea), (II-Ieb), (II-Iec), or (II-Ied)

wherein m is 0, 1, 2 or 3;p is 0, 1, 2, or 3;each R₃₂ is independently halogen, alkyl, hydroxyl, or cyano;or a pharmaceutically acceptable salt thereof,

In some embodiments, the compound of Formula (II-I) is of Formula(II-Iega), (II-Iegb), (II-Iegc), or (II-Iegd),

wherein u is 0, 1, or 2; each X is independently —C(R^(N))—,—C(R^(N))₂—, —O—, —S—, —N—, or N(R^(N))— wherein R^(N) is independentlyhydrogen, substituted or unsubstituted C₁₋₆ alkyl, C(═O)R^(GA),—C(═O)OR^(GA), —C(═O)N(R^(GA))₂, —S(═O)₂R^(GA), or —S(═O)₂N(R^(GA))₂;and each instance of R^(GA) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC₃₋₆ carbocylyl, substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, nitrogen protecting group when attached to nitrogen, or twoR^(GA) groups are taken with the intervening atoms to form a substitutedor unsubstituted heterocyclyl or heteroaryl ring;or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-I) is of Formula(II-Iha), (II-Ihb), (II-Ihc), or (II-Ihd),

wherein each R₃₅ is independently halogen, alkyl, hydroxyl, or cyano;and r is 0, 1, 2 or 3;or a pharmaceutically acceptable salt thereof.In some embodiments, the compound of Formula (II-I) is of Formula(II-Iia), (II-Iib), (II-Iic), or (II-Iid),

wherein s is 0, 1, or 2; each X is independently —C(R^(N))—,—C(R^(N))₂—, —O—, —S—, —N—, or N(R^(N))— wherein R^(N) is independentlyhydrogen, substituted or unsubstituted C1-6 alkyl, C(═O)R^(GA),—C(═O)OR^(GA), —C(═O)N(R^(GA))₂, —S(═O)₂R^(GA), or —S(═O)₂N(R^(GA))₂;and each instance of R^(GA) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC3.6 carbocylyl, substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, nitrogen protecting group when attached to nitrogen, or twoR^(GA) groups are taken with the intervening atoms to form a substitutedor unsubstituted heterocyclyl or heteroaryl ring;or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-II) is of Formula(II-IIa), (II-IIaa), (II-IIab), (II-IIac), (II-IIad) or (II-IIae),

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-II) is of Formula(II-IIna), (II-IInb), (II-IInc), (II-IInd), or (II-IIne)

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-II) is of Formula(II-IIma), (II-IImb), (II-IImc), (II-IImd), (II-IIme), (II-IImf),(II-IImg), (II-IImh), (II-IImi), or (II-IImj),

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-II) is of Formula(II-IIpa), (II-IIpb), (II-IIpc), (II-IIpd), (II-IIpe), (II-IIpf),(II-IIpg), (II-IIph), (II-IIpi), (II-IIpj), or (II-IIpk),

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-II) is of Formula(II-IIwa), (II-IIwb), (II-IIwc), (II-IIwd), (II-IIwe), (II-IIwf),(II-IIwg), (II-IIwh), (II-IIwi), (II-IIwj), or (II-IIwk),

wherein m is 0, 1, 2 or 3;p is 0, 1, 2, or 3;each R₃₂ is independently halogen, alkyl, hydroxyl, or cyano;or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II-II) is of Formula(II-IIega), (II-IIegb), (II-IIege), (II-IIegd), (II-IIege), (II-IIegf),(II-IIegg), (II-IIegh), (II-IIegi), (II-IIegj), or (II-IIegk)

wherein u is 0, 1, or 2; each X is independently —C(R^(N))—,—C(R^(N))₂—, —O—, —S—, —N—, or N(R^(N))— wherein R^(N) is independentlyhydrogen, substituted or unsubstituted C1.6 alkyl, C(═O)R^(GA),—C(═O)OR^(GA), —C(═O)N(R^(GA))₂, —S(═O)₂R^(GA), or —S(═O)₂N(R^(GA))₂;and each instance of R^(GA) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstitutedC3.6 carbocylyl, substituted or unsubstituted 3- to 6-memberedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, an oxygen protecting group when attached tooxygen, nitrogen protecting group when attached to nitrogen, or twoR^(GA) groups are taken with the intervening atoms to form a substitutedor unsubstituted heterocyclyl or heteroaryl ring;or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein is a pharmaceutically acceptable salt ofa compound described herein (e.g., a compound of Formula (I-I), (I-II),(I-III), (I-IV), (II-I), (II-II), or (II-III)).

In one aspect, provided herein is a pharmaceutical compositioncomprising a compound described herein (e.g., a compound of Formula(I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. In certain embodiments, the compound of thepresent invention is provided in an effective amount in thepharmaceutical composition. In certain embodiments, the compound of thepresent invention is provided in a therapeutically effective amount. Incertain embodiments, the compound of the present invention is providedin a prophylactically effective amount.

Compounds of the present invention as described herein, act, in certainembodiments, as GAB_(A) modulators, e.g., effecting the GABA_(A)receptor in either a positive or negative manner. As modulators of theexcitability of the central nervous system (CNS), as mediated by theirability to modulate GABA_(A) receptor, such compounds are expected tohave CNS-activity.

Thus, in another aspect, provided are methods of treating a CNS-relateddisorder in a subject in need thereof, comprising administering to thesubject an effective amount of a compound of the present invention. Incertain embodiments, CNS-related disorder is a sleep disorder, a mooddisorder, a schizophrenia spectrum disorder, a convulsive disorder, adisorder of memory and/or cognition, a movement disorder, a personalitydisorder, autism spectrum disorder, pain, traumatic brain injury, avascular disease, a substance abuse disorder and/or withdrawal syndrome,tinnitus, or status epilepticus. In certain embodiments, the CNS-relateddisorder is depression. In certain embodiments, the CNS-related disorderis postpartum depression. In certain embodiments, the CNS-relateddisorder is major depressive disorder. In certain embodiments, the majordepressive disorder is moderate major depressive disorder. In certainembodiments, the major depressive disorder is severe major depressivedisorder. In certain embodiments, the compound is administered orally,subcutaneously, intravenously, or intramuscularly. In certainembodiments, the compound is administered orally. In certainembodiments, the compound is administered chronically. In certainembodiments, the compound is administered continuously, e.g., bycontinuous intravenous infusion.

Exemplary compounds of the invention may be synthesized from thefollowing known starting materials using methods known to one skilled inthe art or certain references.

In one aspect, provided herein is a pharmaceutically acceptable salt ofa compound described herein (e.g., a compound of Formula (I-I), (I-II),(I-III), (I-IV), (II-I), (II-II), or (II-III).

Alternative Embodiments

In an alternative embodiment, compounds described herein may alsocomprise one or more isotopic substitutions. For example, hydrogen maybe ²H (D or deuterium) or ³H (T or tritium); carbon may be, for example,¹³C or ¹⁴C; oxygen may be, for example, ¹⁸O; nitrogen may be, forexample, ¹⁵N, and the like. In other embodiments, a particular isotope(e.g., ³H, ¹³C, ¹⁸O, or ¹⁵N) can represent at least 1%, at least 5%, atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95%, at least 99%, or at least 99.9% of the totalisotopic abundance of an element that occupies a specific site of thecompound.

Pharmaceutical Compositions

In one aspect, provided herein is a pharmaceutical compositioncomprising a compound described herein (e.g., a compound of Formula(I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. In certain embodiments, the compound of thepresent invention is provided in an effective amount in thepharmaceutical composition. In certain embodiments, the compound of thepresent invention is provided in a therapeutically effective amount. Incertain embodiments, the compound of the present invention is providedin a prophylactically effective amount.

In certain embodiments, the pharmaceutical composition comprises aneffective amount of the active ingredient. In certain embodiments, thepharmaceutical composition comprises a therapeutically effective amountof the active ingredient. In certain embodiments, the pharmaceuticalcomposition comprises a prophylactically effective amount of the activeingredient.

The pharmaceutical compositions provided herein can be administered by avariety of routes including, but not limited to, oral (enteral)administration, parenteral (by injection) administration, rectaladministration, transdermal administration, intradermal administration,intrathecal administration, subcutaneous (SC) administration,intravenous (IV) administration, intramuscular (IM) administration, andintranasal administration.

Generally, the compounds provided herein are administered in aneffective amount. The amount of the compound actually administered willtypically be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the like.

When used to prevent the onset of a CNS-disorder, the compounds providedherein will be administered to a subject at risk for developing thecondition, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Subjects at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

The pharmaceutical compositions provided herein can also be administeredchronically (“chronic administration”). Chronic administration refers toadministration of a compound or pharmaceutical composition thereof overan extended period of time, e.g., for example, over 3 months, 6 months,1 year, 2 years, 3 years, 5 years, etc, or may be continuedindefinitely, for example, for the rest of the subject's life. Incertain embodiments, the chronic administration is intended to provide aconstant level of the compound in the blood, e.g., within thetherapeutic window over the extended period of time.

The pharmaceutical compositions of the present invention may be furtherdelivered using a variety of dosing methods. For example, in certainembodiments, the pharmaceutical composition may be given as a bolus,e.g., in order to raise the concentration of the compound in the bloodto an effective level. The placement of the bolus dose depends on thesystemic levels of the active ingredient desired throughout the body,e.g., an intramuscular or subcutaneous bolus dose allows a slow releaseof the active ingredient, while a bolus delivered directly to the veins(e.g., through an IV drip) allows a much faster delivery which quicklyraises the concentration of the active ingredient in the blood to aneffective level. In other embodiments, the pharmaceutical compositionmay be administered as a continuous infusion, e.g., by IV drip, toprovide maintenance of a steady-state concentration of the activeingredient in the subject's body. Furthermore, in still yet otherembodiments, the pharmaceutical composition may be administered as firstas a bolus dose, followed by continuous infusion.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, the compound is usually aminor component (from about 0.1 to about 50% by weight or preferablyfrom about 1 to about 40% by weight) with the remainder being variousvehicles or excipients and processing aids helpful for forming thedesired dosing form.

With oral dosing, one to five and especially two to four and typicallythree oral doses per day are representative regimens. Using these dosingpatterns, each dose provides from about 0.01 to about 20 mg/kg of thecompound provided herein, with preferred doses each providing from about0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses, generally in anamount ranging from about 0.01 to about 20% by weight, preferably fromabout 0.1 to about 20% by weight, preferably from about 0.1 to about 10%by weight, and more preferably from about 0.5 to about 15% by weight.

Injection dose levels range from about 0.1 mg/kg/hour to at least 20mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kgor more may also be administered to achieve adequate steady statelevels. The maximum total dose is not expected to exceed about 5 g/dayfor a 40 to 80 kg human patient.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable excipients knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable excipient and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s). When formulated as anointment, the active ingredients will typically be combined with eithera paraffinic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream with,for example an oil-in-water cream base. Such transdermal formulationsare well-known in the art and generally include additional ingredientsto enhance the dermal penetration of stability of the active ingredientsor Formulation. All such known transdermal formulations and ingredientsare included within the scope provided herein.

The compounds provided herein can also be administered by a transdermaldevice. Accordingly, transdermal administration can be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The compounds of the present invention can also be administered insustained release forms or from sustained release drug delivery systems.A description of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The present invention also relates to the pharmaceutically acceptableacid addition salt of a compound of the present invention. The acidwhich may be used to prepare the pharmaceutically acceptable salt isthat which forms a non-toxic acid addition salt, i.e., a salt containingpharmacologically acceptable anions such as the hydrochloride,hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate,acetate, lactate, citrate, tartrate, succinate, maleate, fumarate,benzoate, para-toluenesulfonate, and the like.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of the present invention and a pharmaceuticallyacceptable excipient, e.g., a composition suitable for injection, suchas for intravenous (IV) administration.

Pharmaceutically acceptable excipients include any and all diluents orother liquid vehicles, dispersion or suspension aids, surface activeagents, isotonic agents, preservatives, lubricants and the like, assuited to the particular dosage form desired, e.g., injection. Generalconsiderations in the formulation and/or manufacture of pharmaceuticalcompositions agents can be found, for example, in Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980), and Remington: The Science andPractice of Pharmacy, 21^(st) Edition (Lippincott Williams & Wilkins,2005).

For example, injectable preparations, such as sterile injectable aqueoussuspensions, can be formulated according to the known art using suitabledispersing or wetting agents and suspending agents. Exemplary excipientsthat can be employed include, but are not limited to, water, sterilesaline or phosphate-buffered saline, or Ringer's solution.

In certain embodiments, the pharmaceutical composition further comprisesa cyclodextrin derivative. The most common cyclodextrins are α-, β- andγ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucose units,respectively, optionally comprising one or more substituents on thelinked sugar moieties, which include, but are not limited to,substituted or unsubstituted methylated, hydroxyalkylated, acylated, andsulfoalkylether substitution. In certain embodiments, the cyclodextrinis a sulfoalkyl ether β-cyclodextrin, e.g., for example, sulfobutylether β-cyclodextrin, also known as CAPTISOL®. See, e.g., U.S. Pat. No.5,376,645. In certain embodiments, the composition compriseshexapropyl-β-cyclodextrin. In a more particular embodiment, thecomposition comprises hexapropyl-β-cyclodextrin (10-50% in water).

The injectable composition can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

Generally, the compounds provided herein are administered in aneffective amount. The amount of the compound actually administered willtypically be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered, the age, weight,response of the individual patient, the severity of the patient'ssymptoms, and the like.

The compositions are presented in unit dosage forms to facilitateaccurate dosing. The term “unit dosage forms” refers to physicallydiscrete units suitable as unitary dosages for human subjects and othermammals, each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include pre-filled, pre-measured ampules or syringes of theliquid compositions. In such compositions, the compound is usually aminor component (from about 0.1% to about 50% by weight or preferablyfrom about 1% to about 40% by weight) with the remainder being variousvehicles or carriers and processing aids helpful for forming the desireddosing form.

As used herein, an “episodic dosing regimen” is a dosing regimen whereina compound of Formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II),or (II-III) or a composition comprising a compound of Formula (I-I),(I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III) is administered toa subject for a finite period of time in response to the diagnosis of adisorder or symptom thereof, e.g, a diagnosis or symptom of depression.an episode of major depressive disorder, bipolar depression, anxiety, orpostpartum depression. In some embodiments, the major depressivedisorder is moderate major depressive disorder. In some embodiments, themajor depressive disorder is severe major depressive disorder. In someembodiments, the compound is formulated as individual dosage units, eachunit comprising a compound of Formula (I-I), (I-II), (I-III), (I-IV),(II-I), (II-II), or (II-III) and one or more suitable pharmaceuticalexcipients. In some embodiments, the episodic dosing regimen has aduration of a plurality of weeks, e.g. about 8 weeks. In contrast withchronic administration as defined herein, episodic dosing of a compoundoccurs over a finite period of time, e.g., from about 2 weeks to about 8weeks, in response to a diagnosis of a disorder, e.g., depression, or asymptom thereof. In some embodiments, episodic dosing occurs once perday across a plurality of weeks, e.g., from about 2 weeks to about 6weeks. In one embodiment, the episodic dosing has a duration of twoweeks. In some embodiments, more than one episodic dosing regimen isadministered to the subject, e.g., two or more episodic regimensthroughout the subject's life

The compounds provided herein can be administered as the sole activeagent, or they can be administered in combination with other activeagents. In one aspect, the present invention provides a combination of acompound of the present invention and another pharmacologically activeagent. Administration in combination can proceed by any techniqueapparent to those of skill in the art including, for example, separate,sequential, concurrent, and alternating administration.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.General considerations in the formulation and/or manufacture ofpharmaceutical compositions can be found, for example, in Remington: TheScience and Practice of Pharmacy 21^(st) ed., Lippincott Williams &Wilkins, 2005.

In one aspect, provided is a kit comprising a composition (e.g., a solidcomposition) comprising a compound of Formula (I-I), (I-II), (I-III),(I-IV), (II-I), (II-II), or (II-III).

Methods of Use and Treatment

In an aspect, compounds described herein, e.g., compounds of Formula(I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III), areenvisioned to be useful as therapeutic agents for treating a CNS-relateddisorder (e.g., sleep disorder, a mood disorder such as depression, aschizophrenia spectrum disorder, a convulsive disorder, epileptogenesis,a disorder of memory and/or cognition, a movement disorder, apersonality disorder, autism spectrum disorder, pain, traumatic braininjury, a vascular disease, a substance abuse disorder and/or withdrawalsyndrome, or tinnitus) in a subject in need (e.g., a subject with Rettsyndrome, Fragile X syndrome, or Angelman syndrome). Exemplary CNSconditions related to GABA-modulation include, but are not limited to,sleep disorders [e.g., insomnia], mood disorders [e.g., depression(e.g., major depressive disorder (MDD)), dysthymic disorder (e.g., milddepression), bipolar disorder (e.g., I and/or II), anxiety disorders(e.g., generalized anxiety disorder (GAD), social anxiety disorder),stress, post-traumatic stress disorder (PTSD), compulsive disorders(e.g., obsessive compulsive disorder (OCD))], schizophrenia spectrumdisorders [e.g., schizophrenia, schizoaffective disorder], convulsivedisorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures],disorders of memory and/or cognition [e.g., attention disorders (e.g.,attention deficit hyperactivity disorder (ADHD)), dementia (e.g.,Alzheimer's type dementia, Lewis body type dementia, vascular typedementia], movement disorders [e.g., Huntington's disease, Parkinson'sdisease], personality disorders [e.g., anti-social personality disorder,obsessive compulsive personality disorder], autism spectrum disorders(ASD) [e.g., autism, monogenetic causes of autism such assynaptophathy's, e.g., Rett syndrome, Fragile X syndrome, Angelmansyndrome], pain [e.g., neuropathic pain, injury related pain syndromes,acute pain, chronic pain], traumatic brain injury (TBI), vasculardiseases [e.g., stroke, ischemia, vascular malformations], substanceabuse disorders and/or withdrawal syndromes [e.g., addition to opiates,cocaine, and/or alcohol], and tinnitus.

In certain embodiments, CNS-related disorder is a sleep disorder, a mooddisorder, a schizophrenia spectrum disorder, a convulsive disorder, adisorder of memory and/or cognition, a movement disorder, a personalitydisorder, autism spectrum disorder, pain, traumatic brain injury, avascular disease, a substance abuse disorder and/or withdrawal syndrome,tinnitus, or status epilepticus. In certain embodiments, the CNS-relateddisorder is depression. In certain embodiments, the CNS-related disorderis postpartum depression. In certain embodiments, the CNS-relateddisorder is major depressive disorder. In certain embodiments, the majordepressive disorder is moderate major depressive disorder. In certainembodiments, the major depressive disorder is severe major depressivedisorder.

In an aspect, provided is a method of alleviating or preventing seizureactivity in a subject, comprising administering to the subject in needof such treatment an effective amount of a compound of the presentinvention. In some embodiments, the method alleviates or preventsepileptogenesis.

In yet another aspect, provided is a combination of a compound of thepresent invention and another pharmacologically active agent. Thecompounds provided herein can be administered as the sole active agentor they can be administered in combination with other agents.Administration in combination can proceed by any technique apparent tothose of skill in the art including, for example, separate, sequential,concurrent and alternating administration.

In another aspect, provided is a method of treating or preventing brainexcitability in a subject susceptible to or afflicted with a conditionassociated with brain excitability, comprising administering to thesubject an effective amount of a compound of the present invention tothe subject.

In yet another aspect, provided is a method of treating or preventingstress or anxiety in a subject, comprising administering to the subjectin need of such treatment an effective amount of a compound of thepresent invention, or a composition thereof.

In yet another aspect, provided is a method of alleviating or preventinginsomnia in a subject, comprising administering to the subject in needof such treatment an effective amount of a compound of the presentinvention, or a composition thereof.

In yet another aspect, provided is a method of inducing sleep andmaintaining substantially the level of REM sleep that is found in normalsleep, wherein substantial rebound insomnia is not induced, comprisingadministering an effective amount of a compound of the presentinvention.

In yet another aspect, provided is a method of alleviating or preventingpremenstrual syndrome (PMS) or postnatal depression (PND) in a subject,comprising administering to the subject in need of such treatment aneffective amount of a compound of the present invention.

In yet another aspect, provided is a method of treating or preventingmood disorders in a subject, comprising administering to the subject inneed of such treatment an effective amount of a compound of the presentinvention. In certain embodiments the mood disorder is depression.

In yet another aspect, provided is a method of cognition enhancement ortreating memory disorder by administering to the subject atherapeutically effective amount of a compound of the present invention.In certain embodiments, the disorder is Alzheimer's disease. In certainembodiments, the disorder is Rett syndrome.

In yet another aspect, provided is a method of treating attentiondisorders by administering to the subject a therapeutically effectiveamount of a compound of the present invention. In certain embodiments,the attention disorder is ADHD.

In certain embodiments, the compound is administered to the subjectchronically. In certain embodiments, the compound is administered to thesubject orally, subcutaneously, intramuscularly, or intravenously.

Neuroendocrine Disorders and Dysfunction

Provided herein are methods that can be used for treating neuroendocrinedisorders and dysfunction. As used herein, “neuroendocrine disorder” or“neuroendocrine dysfunction” refers to a variety of conditions caused byimbalances in the body's hormone production directly related to thebrain. Neuroendocrine disorders involve interactions between the nervoussystem and the endocrine system. Because the hypothalamus and thepituitary gland are two areas of the brain that regulate the productionof hormones, damage to the hypothalamus or pituitary gland, e.g., bytraumatic brain injury, may impact the production of hormones and otherneuroendocrine functions of the brain. In some embodiments, theneuroendocrine disorder or dysfunction is associated with a women'shealth disorder or condition (e.g., a women's health disorder orcondition described herein). In some embodiments, the neuroendocrinedisorder or dysfunction is associated with a women's health disorder orcondition is polycystic ovary syndrome.

Symptoms of neuroendocrine disorder include, but are not limited to,behavioral, emotional, and sleep-related symptoms, symptoms related toreproductive function, and somatic symptoms; including but not limitedto fatigue, poor memory, anxiety, depression, weight gain or loss,emotional lability, lack of concentration, attention difficulties, lossof lipido, infertility, amenorrhea, loss of muscle mass, increased bellybody fat, low blood pressure, reduced heart rate, hair loss, anemia,constipation, cold intolerance, and dry skin.

Neurodegenerative Diseases and Disorders

The methods described herein can be used for treating neurodegenerativediseases and disorders. The term “neurodegenerative disease” includesdiseases and disorders that are associated with the progressive loss ofstructure or function of neurons, or death of neurons. Neurodegenerativediseases and disorders include, but are not limited to, Alzheimer'sdisease (including the associated symptoms of mild, moderate, or severecognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic andischemic injuries; ataxia and convulsion (including for the treatmentand prevention and prevention of seizures that are caused byschizoaffective disorder or by drugs used to treat schizophrenia);benign forgetfulness; brain edema; cerebellar ataxia including McLeodneuroacanthocytosis syndrome (MLS); closed head injury; coma; contusiveinjuries (e.g., spinal cord injury and head injury); dementias includingmulti-infarct dementia and senile dementia; disturbances ofconsciousness; Down syndrome; drug-induced or medication-inducedParkinsonism (such as neuroleptic-induced acute akathisia, acutedystonia, Parkinsonism, or tardive dyskinesia, neuroleptic malignantsyndrome, or medication-induced postural tremor); epilepsy; fragile Xsyndrome; Gilles de la Tourette's syndrome; head trauma; hearingimpairment and loss; Huntington's disease; Lennox syndrome;levodopa-induced dyskinesia; mental retardation; movement disordersincluding akinesias and akinetic (rigid) syndromes (including basalganglia calcification, corticobasal degeneration, multiple systematrophy, Parkinsonism-ALS dementia complex, Parkinson's disease,postencephalitic parkinsonism, and progressively supranuclear palsy);muscular spasms and disorders associated with muscular spasticity orweakness including chorea (such as benign hereditary chorea,drug-induced chorea, hemiballism, Huntington's disease,neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea),dyskinesia (including tics such as complex tics, simple tics, andsymptomatic tics), myoclonus (including generalized myoclonus and focalcyloclonus), tremor (such as rest tremor, postural tremor, and intentiontremor) and dystonia (including axial dystonia, dystonic writer's cramp,hemiplegic dystonia, paroxysmal dystonia, and focal dystonia such asblepharospasm, oromandibular dystonia, and spasmodic dysphonia andtorticollis); neuronal damage including ocular damage, retinopathy ormacular degeneration of the eye; neurotoxic injury which followscerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebralischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia,perinatal asphyxia and cardiac arrest; Parkinson's disease; seizure;status epilecticus; stroke; tinnitus; tubular sclerosis, and viralinfection induced neurodegeneration (e.g., caused by acquiredimmunodeficiency syndrome (AIDS) and encephalopathies).Neurodegenerative diseases also include, but are not limited to,neurotoxic injury which follows cerebral stroke, thromboembolic stroke,hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia,amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest. Methodsof treating or preventing a neurodegenerative disease also includetreating or preventing loss of neuronal function characteristic ofneurodegenerative disorder.

Mood Disorders

Also provided herein are methods for treating a mood disorder, forexample clinical depression, postnatal depression or postpartumdepression, perinatal depression, atypical depression, melancholicdepression, psychotic major depression, cataonic depression, seasonalaffective disorder, dysthymia, double depression, depressive personalitydisorder, recurrent brief depression, minor depressive disorder, bipolardisorder or manic depressive disorder, depression caused by chronicmedical conditions, treatment-resistant depression, refractorydepression, suicidality, suicidal ideation, or suicidal behavior. Insome embodiments, the method described herein provides therapeuticeffect to a subject suffering from depression (e.g., moderate or severedepression). In some embodiments, the mood disorder is associated with adisease or disorder described herein (e.g., neuroendocrine diseases anddisorders, neurodegenerative diseases and disorders (e.g., epilepsy),movement disorders, tremor (e.g., Parkinson's Disease), women's healthdisorders or conditions).

Clinical depression is also known as major depression, major depressivedisorder (MDD), severe depression, unipolar depression, unipolardisorder, and recurrent depression, and refers to a mental disordercharacterized by pervasive and persistent low mood that is accompaniedby low self-esteem and loss of interest or pleasure in normallyenjoyable activities. Some people with clinical depression have troublesleeping, lose weight, and generally feel agitated and irritable.Clinical depression affects how an individual feels, thinks, and behavesand may lead to a variety of emotional and physical problems.Individuals with clinical depression may have trouble doing day-to-dayactivities and make an individual feel as if life is not worth living.

Peripartum depression refers to depression in pregnancy. Symptomsinclude irritability, crying, feeling restless, trouble sleeping,extreme exhaustion (emotional and/or physical), changes in appetite,difficulty focusing, increased anxiety and/or worry, disconnectedfeeling from baby and/or fetus, and losing interest in formerlypleasurable activities.

Postnatal depression (PND) is also referred to as postpartum depression(PPD), and refers to a type of clinical depression that affects womenafter childbirth. Symptoms can include sadness, fatigue, changes insleeping and eating habits, reduced sexual desire, crying episodes,anxiety, and irritability. In some embodiments, the PND is atreatment-resistant depression (e.g., a treatment-resistant depressionas described herein). In some embodiments, the PND is refractorydepression (e.g., a refractory depression as described herein).

In some embodiments, a subject having PND also experienced depression,or a symptom of depression during pregnancy. This depression is referredto herein as) perinatal depression. In an embodiment, a subjectexperiencing perinatal depression is at increased risk of experiencingPND.

Atypical depression (AD) is characterized by mood reactivity (e.g.,paradoxical anhedonia) and positivity, significant weight gain orincreased appetite. Patients suffering from AD also may have excessivesleep or somnolence (hypersomnia), a sensation of limb heaviness, andsignificant social impairment as a consequence of hypersensitivity toperceived interpersonal rejection.

Melancholic depression is characterized by loss of pleasure (anhedonia)in most or all activities, failures to react to pleasurable stimuli,depressed mood more pronounced than that of grief or loss, excessiveweight loss, or excessive guilt.

Psychotic major depression (PMD) or psychotic depression refers to amajor depressive episode, in particular of melancholic nature, where theindividual experiences psychotic symptoms such as delusions andhallucinations.

Catatonic depression refers to major depression involving disturbancesof motor behavior and other symptoms. An individual may become mute andstuporose, and either is immobile or exhibits purposeless or bizarremovements.

Seasonal affective disorder (SAD) refers to a type of seasonaldepression wherein an individual has seasonal patterns of depressiveepisodes coming on in the fall or winter.

Dysthymia refers to a condition related to unipolar depression, wherethe same physical and cognitive problems are evident. They are not assevere and tend to last longer (e.g., at least 2 years).

Double depression refers to fairly depressed mood (dysthymia) that lastsfor at least 2 years and is punctuated by periods of major depression.

Depressive Personality Disorder (DPD) refers to a personality disorderwith depressive features.

Recurrent Brief Depression (RBD) refers to a condition in whichindividuals have depressive episodes about once per month, each episodelasting 2 weeks or less and typically less than 2-3 days.

Minor depressive disorder or minor depression refers to a depression inwhich at least 2 symptoms are present for 2 weeks.

Bipolar disorder or manic depressive disorder causes extreme mood swingsthat include emotional highs (mania or hypomania) and lows (depression).During periods of mania the individual may feel or act abnormally happy,energetic, or irritable. They often make poorly thought out decisionswith little regard to the consequences. The need for sleep is usuallyreduced. During periods of depression there may be crying, poor eyecontact with others, and a negative outlook on life. The risk of suicideamong those with the disorder is high at greater than 6% over 20 years,while self-harm occurs in 30-40%. Other mental health issues such asanxiety disorder and substance use disorder are commonly associated withbipolar disorder.

Depression caused by chronic medical conditions refers to depressioncaused by chronic medical conditions such as cancer or chronic pain,chemotherapy, chronic stress.

Treatment-resistant depression refers to a condition where theindividuals have been treated for depression, but the symptoms do notimprove. For example, antidepressants or psychological counseling(psychotherapy) do not ease depression symptoms for individuals withtreatment-resistant depression. In some cases, individuals withtreatment-resistant depression improve symptoms, but come back.Refractory depression occurs in patients suffering from depression whoare resistant to standard pharmacological treatments, includingtricyclic antidepressants, MAOIs, SSRIs, and double and triple uptakeinhibitors and/or anxiolytic drugs, as well as non-pharmacologicaltreatments (e.g., psychotherapy, electroconvulsive therapy, vagus nervestimulation and/or transcranial magnetic stimulation).

Post-surgical depression refers to feelings of depression that follow asurgical procedure (e.g., as a result of having to confront one'smortality). For example, individuals may feel sadness or empty moodpersistently, a loss of pleasure or interest in hobbies and activitiesnormally enjoyed, or a persistent felling of worthlessness orhopelessness.

Mood disorder associated with conditions or disorders of women's healthrefers to mood disorders (e.g., depression) associated with (e.g.,resulting from) a condition or disorder of women's health (e.g., asdescribed herein).

Suicidality, suicidal ideation, suicidal behavior refers to the tendencyof an individual to commit suicide. Suicidal ideation concerns thoughtsabout or an unusual preoccupation with suicide. The range of suicidalideation varies greatly, from e.g., fleeting thoughts to extensivethoughts, detailed planning, role playing, incomplete attempts.

Symptoms include talking about suicide, getting the means to commitsuicide, withdrawing from social contact, being preoccupied with death,feeling trapped or hopeless about a situation, increasing use of alcoholor drugs, doing risky or self-destructive things, saying goodbye topeople as if they won't be seen again.

Symptoms of depression include persistent anxious or sad feelings,feelings of helplessness, hopelessness, pessimism, worthlessness, lowenergy, restlessness, difficulty sleeping, sleeplessness, irritability,fatigue, motor challenges, loss of interest in pleasurable activities orhobbies, loss of concentration, loss of energy, poor self-esteem,absence of positive thoughts or plans, excessive sleeping, overeating,appetite loss, insomnia, self-harm, thoughts of suicide, and suicideattempts. The presence, severity, frequency, and duration of symptomsmay vary on a case to case basis. Symptoms of depression, and relief ofthe same, may be ascertained by a physician or psychologist (e.g., by amental state examination).

In some embodiments, the method comprises monitoring a subject with aknown depression scale, e.g., the Hamilton Depression (HAM-D) scale, theClinical Global Impression-Improvement Scale (CGI), and theMontgomery-Åsberg Depression Rating Scale (MADRS). In some embodiments,a therapeutic effect can be determined by reduction in HamiltonDepression (HAM-D) total score exhibited by the subject. Reduction inthe HAM-D total score can happen within 4, 3, 2, or 1 days; or 96, 84,72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less. The therapeutic effectcan be assessed across a specified treatment period. For example, thetherapeutic effect can be determined by a decrease from baseline inHAM-D total score after administering a compound described herein, e.g.,a compound of Formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II),or (II-III) (e.g., 12, 24, or 48 hours after administration; or 24, 48,72, or 96 hours or more; or 1 day, 2 days, 14 days, 21 days, or 28 days;or 1 week, 2 weeks, 3 weeks, or 4 weeks; or 1 month, 2 months, 6 months,or 10 months; or 1 year, 2 years, or for life).

In some embodiments, the subject has a mild depressive disorder, e.g.,mild major depressive disorder. In some embodiments, the subject has amoderate depressive disorder, e.g., moderate major depressive disorder.In some embodiments, the subject has a severe depressive disorder, e.g.,severe major depressive disorder. In some embodiments, the subject has avery severe depressive disorder, e.g., very severe major depressivedisorder. In some embodiments, the baseline HAM-D total score of thesubject (i.e., prior to treatment with a compound described herein,e.g., a compound of Formula (I-I), (I-II), (I-III), (I-IV), (II-I),(II-II), or (II-III)) is at least 24. In some embodiments, the baselineHAM-D total score of the subject is at least 18. In some embodiments,the baseline HAM-D total score of the subject is between and including14 and 18. In some embodiments, the baseline HAM-D total score of thesubject is between and including 19 and 22. In some embodiments, theHAM-D total score of the subject before treatment with a compounddescribed herein, e.g., a compound of Formula (I-I), (I-II), (I-III),(I-IV), (II-I), (II-II), or (II-III), is greater than or equal to 23. Insome embodiments, the baseline score is at least 10, 15, or 20. In someembodiments, the HAM-D total score of the subject after treatment with acompound described herein, e.g., a compound of Formula (I-I), (I-II),(I-III), (I-IV), (II-I), (II-II), or (II-III), is about 0 to 10 (e.g.,less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8). In someembodiments, the HAM-D total score after treatment with a compounddescribed herein, e.g., a compound of Formula (I-I), (I-II), (I-III),(I-IV), (II-I), (II-II), or (II-III), is less than 10, 7, 5, or 3. Insome embodiments, the decrease in HAM-D total score is from a baselinescore of about 20 to 30 (e.g., 22 to 28, 23 to 27, 24 to 27, 25 to 27,26 to 27) to a HAM-D total score at about 0 to 10 (e.g., less than 10; 0to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8) after treatment with acompound described herein, e.g., a compound of Formula (I-I), (I-II),(I-III), (I-IV), (II-I), (II-II), or (II-III). In some embodiments, thedecrease in the baseline HAM-D total score to HAM-D total score aftertreatment with a compound described herein, e.g., a compound of Formula(I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III), is atleast 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100 fold). In someembodiments, the percentage decrease in the baseline HAM-D total scoreto HAM-D total score after treatment with a compound described herein,e.g., a compound of Formula (I-I), (I-II), (I-III), (I-IV), (II-I),(II-II), or (II-III), is at least 50% (e.g., 60%, 70%, 80%, or 90%). Insome embodiments, the therapeutic effect is measured as a decrease inthe HAM-D total score after treatment with a compound described herein,e.g., a compound of Formula (I-I), (I-II), (I-III), (I-IV), (II-I),(II-II), or (II-III), relative to the baseline HAM-D total score (e.g.,12, 24, 48 hours after administration; or 24, 48, 72, 96 hours or more;or 1 day, 2 days, 14 days, or more) is at least 10, 15, or 20 points.

In some embodiments, the method of treating a depressive disorder, e.g.,major depressive disorder provides a therapeutic effect (e.g., asmeasured by reduction in Hamilton Depression Score (HAM-D)) within 14,10, 4, 3, 2, or 1 days, or 24, 20, 16, 12, 10, or 8 hours or less. Insome embodiments, the method of treating the depressive disorder, e.g.,major depressive disorder, provides a therapeutic effect (e.g., asdetermined by a statistically significant reduction in HAM-D totalscore) within the first or second day of the treatment with a compounddescribed herein, e.g., a compound of Formula (I-I), (I-II), (I-III),(I-IV), (II-I), (II-II), or (II-III). In some embodiments, the method oftreating the depressive disorder, e.g., major depressive disorder,provides a therapeutic effect (e.g., as determined by a statisticallysignificant reduction in HAM-D total score) within less than or equal to14 days since the beginning of the treatment with a compound describedherein, e.g., a compound of Formula (I-I), (I-II), (I-III), (I-IV),(II-I), (II-II), or (II-III). In some embodiments, the method oftreating the depressive disorder, e.g., major depressive disorder,provides a therapeutic effect (e.g., as determined by a statisticallysignificant reduction in HAM-D total score) within less than or equal to21 days since the beginning of the treatment with a compound describedherein, e.g., a compound of Formula (I-I), (I-II), (I-III), (I-IV),(II-I), (II-II), or (II-III). In some embodiments, the method oftreating the depressive disorder, e.g., major depressive disorder,provides a therapeutic effect (e.g., as determined by a statisticallysignificant reduction in HAM-D total score) within less than or equal to28 days since the beginning of the treatment with a compound describedherein, e.g., a compound of Formula (I-I), (I-II), (I-III), (I-IV),(II-I), (II-II), or (II-III). In some embodiments, the therapeuticeffect is a decrease from baseline in HAM-D total score after treatmentwith a compound described herein, e.g., a compound of Formula (I-I),(I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III). (e.g., treatmentwith a compound described herein, e.g., a compound of Formula (I-I),(I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III)), once a day for14 days). In some embodiments, the HAM-D total score of the subjectbefore treatment with a compound described herein, e.g., a compound ofFormula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III), isat least 24. In some embodiments, the HAM-D total score of the subjectbefore treatment with a compound described herein, e.g., a compound ofFormula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III), isat least 18. In some embodiments, the HAM-D total score of the subjectbefore 10 treatment with a compound described herein, e.g., a compoundof Formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III),is between and including 14 and 18. In some embodiments, the decrease inHAM-D total score after treating the subject with a compound describedherein, e.g., a compound of Formula (I-I), (I-II), (I-III), (I-IV),(II-I), (II-II), or (II-III), relative to the baseline HAM-D total scoreis at least 10. In some embodiments, the decrease in HAM-D total scoreafter treating the subject with a compound described herein, e.g., acompound of Formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or(II-III), relative to the baseline HAM-D total score is at least 15(e.g., at least 17). In some embodiments, the HAM-D total scoreassociated with treating the subject with a compound described herein,e.g., a compound of Formula (I-I), (I-II), (I-III), (I-IV), (II-I),(II-II), or (II-III), is no more than a number ranging from 6 to 8. Insome embodiments, the HAM-D total score associated with treating thesubject with a compound described herein, e.g., a compound of Formula(I-I), (I-II), (I-III), (I-IV), (II-I), (II-II), or (II-III), is no morethan 7.

In some embodiments, the method provides therapeutic effect (e.g., asmeasured by reduction in Clinical Global Impression-Improvement Scale(CGI)) within 14, 10, 4, 3, 2, or 1 days, or 24, 20, 16, 12, 10, or 8hours or less. In some embodiments, the CNS-disorder is a depressivedisorder, e.g., major depressive disorder. In some embodiments, themethod of treating the depressive disorder, e.g., major depressivedisorder provides a therapeutic effect within the second day of thetreatment period. In some embodiments, the therapeutic effect is adecrease from baseline in CGI score at the end of a treatment period(e.g., 14 days after administration).

In some embodiments, the method provides therapeutic effect (e.g., asmeasured by reduction in Montgomery-Åsberg Depression Rating Scale(MADRS)) within 14, 10, 4, 3, 2, or 1 days, or 24, 20, 16, 12, 10, or 8hours or less. In some embodiments, the CNS-disorder is a depressivedisorder, e.g., major depressive disorder. In some embodiments, themethod of treating the depressive disorder, e.g., major depressivedisorder provides a therapeutic effect within the second day of thetreatment period. In some embodiments, the therapeutic effect is adecrease from baseline in MADRS score at the end of a treatment period(e.g., 14 days after administration).

A therapeutic effect for major depressive disorder can be determined bya reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) scoreexhibited by the subject. For example, the MADRS score can be reducedwithin 4, 3, 2, or 1 days; or 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8hours or less. The Montgomery-Åsberg Depression Rating Scale (MADRS) isa ten-item diagnostic questionnaire (regarding apparent sadness,reported sadness, inner tension, reduced sleep, reduced appetite,concentration difficulties, lassitude, inability to feel, pessimisticthoughts, and suicidal thoughts) which psychiatrists use to measure theseverity of depressive episodes in patients with mood disorders.

In some embodiments, the method provides therapeutic effect (e.g., asmeasured by reduction in Edinburgh Postnatal Depression Scale (EPDS))within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less. In someembodiments, the therapeutic effect is an improvement measured by theEPDS.

In some embodiments, the method provides therapeutic effect (e.g., asmeasured by reduction in Generalized Anxiety Disorder 7-Item Scale(GAD-7)) within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less.

Anxiety Disorders

Provided herein are methods for treating anxiety disorders (e.g.,generalized anxiety disorder, panic disorder, obsessive compulsivedisorder, phobia, post-traumatic stress disorder). Anxiety disorder is ablanket term covering several different forms of abnormal andpathological fear and anxiety. Current psychiatric diagnostic criteriarecognize a wide variety of anxiety disorders.

Generalized anxiety disorder is a common chronic disorder characterizedby long-lasting anxiety that is not focused on any one object orsituation. Those suffering from generalized anxiety experiencenon-specific persistent fear and worry and become overly concerned witheveryday matters. Generalized anxiety disorder is the most commonanxiety disorder to affect older adults.

In panic disorder, a person suffers from brief attacks of intense terrorand apprehension, often marked by trembling, shaking, confusion,dizziness, nausea, difficulty breathing. These panic attacks, defined bythe APA as fear or discomfort that abruptly arises and peaks in lessthan ten minutes, can last for several hours and can be triggered bystress, fear, or even exercise; although the specific cause is notalways apparent. In addition to recurrent unexpected panic attacks, adiagnosis of panic disorder also requires that said attacks have chronicconsequences: either worry over the attacks' potential implications,persistent fear of future attacks, or significant changes in behaviorrelated to the attacks. Accordingly, those suffering from panic disorderexperience symptoms even outside of specific panic episodes. Often,normal changes in heartbeat are noticed by a panic sufferer, leadingthem to think something is wrong with their heart or they are about tohave another panic attack. In some cases, a heightened awareness(hypervigilance) of body functioning occurs during panic attacks,wherein any perceived physiological change is interpreted as a possiblelife threatening illness (i.e. extreme hypochondriasis).

Obsessive compulsive disorder is a type of anxiety disorder primarilycharacterized by repetitive obsessions (distressing, persistent, andintrusive thoughts or images) and compulsions (urges to perform specificacts or rituals). The OCD thought pattern may be likened tosuperstitions insofar as it involves a belief in a causativerelationship where, in reality, one does not exist. Often the process isentirely illogical; for example, the compulsion of walking in a certainpattern may be employed to alleviate the obsession of impending harm.And in many cases, the compulsion is entirely inexplicable, simply anurge to complete a ritual triggered by nervousness. In a minority ofcases, sufferers of OCD may only experience obsessions, with no overtcompulsions; a much smaller number of sufferers experience onlycompulsions.

The single largest category of anxiety disorders is that of phobia,which includes all cases in which fear and anxiety is triggered by aspecific stimulus or situation. Sufferers typically anticipateterrifying consequences from encountering the object of their fear,which can be anything from an animal to a location to a bodily fluid.

Post-traumatic stress disorder or PTSD is an anxiety disorder whichresults from a traumatic experience. Post-traumatic stress can resultfrom an extreme situation, such as combat, rape, hostage situations, oreven serious accident. It can also result from long term (chronic)exposure to a severe stressor, for example soldiers who endureindividual battles but cannot cope with continuous combat. Commonsymptoms include flashbacks, avoidant behaviors, and depression.

Women's Health Disorders

Provided herein are methods for treating conditions or disorders relatedto women's health. Conditions or disorders related to women's healthinclude, but are not limited to, gynecological health and disorders(e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder(PMDD)), pregnancy issues (e.g., miscarriage, abortion), infertility andrelated disorders (e.g., polycystic ovary syndrome (PCOS)), otherdisorders and conditions, and issues related to women's overall healthand wellness (e.g., menopause).

Gynecological health and disorders affecting women include menstruationand menstrual irregularities; urinary tract health, including urinaryincontinence and pelvic floor disorders; and such disorders as bacterialvaginosis, vaginitis, uterine fibroids, and vulvodynia.

Premenstrual syndrome (PMS) refers to physical and emotional symptomsthat occur in the one to two weeks before a women's period. Symptomsvary but can include bleeding, mood swings, tender breasts, foodcravings, fatigue, irritability, acne, and depression.

Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. Thesymptoms of PMDD are similar to PMS but more severe and may interferewith work, social activity, and relationships. PMDD symptoms includemood swings, depressed mood or feelings of hopelessness, marked anger,increased interpersonal conflicts, tension and anxiety, irritability,decreased interest in usual activities, difficulty concentrating,fatigue, change in appetite, feeling out of control or overwhelmed,sleep problems, physical problems (e.g., bloating, breast tenderness,swelling, headaches, joint or muscle pain).

Pregnancy issues include preconception care and prenatal care, pregnancyloss (miscarriage and stillbirth), preterm labor and premature birth,sudden infant death syndrome (SIDS), breastfeeding, and birth defects.

Miscarriage refers to a pregnancy that ends on its own, within the first20 weeks of gestation.

Abortion refers to the deliberate termination of a pregnancy, which canbe performed during the first 28 weeks of pregnancy.

Infertility and related disorders include uterine fibroids, polycysticovary syndrome, endometriosis, and primary ovarian insufficiency.

Polycystic ovary syndrome (PCOS) refers to an endocrine system disorderamong women of reproductive age. PCOS is a set of symptoms resultingfrom an elevated male hormone in women. Most women with PCOS grow manysmall cysts on their ovaries.

Symptoms of PCOS include irregular or no menstrual periods, heavyperiods, excess body and facial hair, acne, pelvic pain, difficultygetting pregnant, and patches of thick, darker, velvety skin. PCOS maybe associated with conditions including type 2 diabetes, obesity,obstructive sleep apnea, heart disease, mood disorders, and endometrialcancer.

Other disorders and conditions that affect only women include Turnersyndrome, Rett syndrome, and ovarian and cervical cancers.

Issues related to women's overall health and wellness include violenceagainst women, women with disabilities and their unique challenges,osteoporosis and bone health, and menopause.

Menopause refers to the 12 months after a woman's last menstrual periodand marks the end of menstrual cycles. Menopause typically occurs in awoman's 40s or 50s. Physical symptoms such as hot flashes and emotionalsymptoms of menopause may disrupt sleep, lower energy, or triggeranxiety or feelings of sadness or loss. Menopause includes naturalmenopause and surgical menopause, which is a type of induced menopausedue to an event such as surgery (e.g., hysterectomy, oophorectomy;cancer). It is induced when the ovaries are gravely damaged by, e.g.,radiation, chemotherapy, or other medications.

Epilepsy

The compound of Formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II),or (II-III), or pharmaceutically acceptable salt, or a pharmaceuticallyacceptable composition thereof, can be used in a method describedherein, for example in the treatment of a disorder described herein suchas epilepsy, status epilepticus, or seizure.

Epilepsy is a brain disorder characterized by repeated seizures overtime. Types of epilepsy can include, but are not limited to generalizedepilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy,epilepsy with grand-mal seizures on awakening, West syndrome,Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy,frontal lobe epilepsy, benign focal epilepsy of childhood.

Epileptogenesis

The compounds and methods described herein can be used to treat orprevent epileptogenesis. Epileptogenesis is a gradual process by which anormal brain develops epilepsy (a chronic condition in which seizuresoccur). Epileptogenesis results from neuronal damage precipitated by theinitial insult (e.g., status epilepticus).

Status Epilepticus (SE)

Status epilepticus (SE) can include, e.g., convulsive statusepilepticus, e.g., early status epilepticus, established statusepilepticus, refractory status epilepticus, super-refractory statusepilepticus; non-convulsive status epilepticus, e.g., generalized statusepilepticus, complex partial status epilepticus; generalized periodicepileptiform discharges; and periodic lateralized epileptiformdischarges. Convulsive status epilepticus is characterized by thepresence of convulsive status epileptic seizures, and can include earlystatus epilepticus, established status epilepticus, refractory statusepilepticus, super-refractory status epilepticus. Early statusepilepticus is treated with a first line therapy. Established statusepilepticus is characterized by status epileptic seizures which persistdespite treatment with a first line therapy, and a second line therapyis administered. Refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline and a second line therapy, and a general anesthetic is generallyadministered. Super refractory status epilepticus is characterized bystatus epileptic seizures which persist despite treatment with a firstline therapy, a second line therapy, and a general anesthetic for 24hours or more.

Non-convulsive status epilepticus can include, e.g., focalnon-convulsive status epilepticus, e.g., complex partial non-convulsivestatus epilepticus, simple partial non-convulsive status epilepticus,subtle non-convulsive status epilepticus; generalized non-convulsivestatus epilepticus, e.g., late onset absence non-convulsive statusepilepticus, atypical absence non-convulsive status epilepticus, ortypical absence non-convulsive status epilepticus.

The compound of Formula (I-I), (I-II), (I-III), (I-IV), (II-I), (II-II),or (II-III) or pharmaceutically acceptable salt, or a pharmaceuticallyacceptable composition thereof, can also be administered as aprophylactic to a subject having a CNS disorder e.g., a traumatic braininjury, status epilepticus, e.g., convulsive status epilepticus, e.g.,early status epilepticus, established status epilepticus, refractorystatus epilepticus, super-refractory status epilepticus; non-convulsivestatus epilepticus, e.g., generalized status epilepticus, complexpartial status epilepticus; generalized periodic epileptiformdischarges; and periodic lateralized epileptiform discharges; prior tothe onset of a seizure.

Seizure

A seizure is the physical findings or changes in behavior that occurafter an episode of abnormal electrical activity in the brain. The term“seizure” is often used interchangeably with “convulsion.” Convulsionsare when a person's body shakes rapidly and uncontrollably. Duringconvulsions, the person's muscles contract and relax repeatedly.

Based on the type of behavior and brain activity, seizures are dividedinto two broad categories: generalized and partial (also called local orfocal). Classifying the type of seizure helps doctors diagnose whetheror not a patient has epilepsy.

Generalized seizures are produced by electrical impulses from throughoutthe entire brain, whereas partial seizures are produced (at leastinitially) by electrical impulses in a relatively small part of thebrain. The part of the brain generating the seizures is sometimes calledthe focus.

There are six types of generalized seizures. The most common anddramatic, and therefore the most well-known, is the generalizedconvulsion, also called the grand-mal seizure. In this type of seizure,the patient loses consciousness and usually collapses. The loss ofconsciousness is followed by generalized body stiffening (called the“tonic” phase of the seizure) for 30 to 60 seconds, then by violentjerking (the “clonic” phase) for 30 to 60 seconds, after which thepatient goes into a deep sleep (the “postictal” or after-seizure phase).During grand-mal seizures, injuries and accidents may occur, such astongue biting and urinary incontinence.

Absence seizures cause a short loss of consciousness (just a fewseconds) with few or no symptoms. The patient, most often a child,typically interrupts an activity and stares blankly. These seizuresbegin and end abruptly and may occur several times a day. Patients areusually not aware that they are having a seizure, except that they maybe aware of “losing time.”

Myoclonic seizures consist of sporadic jerks, usually on both sides ofthe body. Patients sometimes describe the jerks as brief electricalshocks. When violent, these seizures may result in dropping orinvoluntarily throwing objects.

Clonic seizures are repetitive, rhythmic jerks that involve both sidesof the body at the same time.

Tonic seizures are characterized by stiffening of the muscles.

Atonic seizures consist of a sudden and general loss of muscle tone,particularly in the arms and legs, which often results in a fall.

Seizures described herein can include epileptic seizures; acuterepetitive seizures; cluster seizures; continuous seizures; unremittingseizures; prolonged seizures; recurrent seizures; status epilepticusseizures, e.g., refractory convulsive status epilepticus, non-convulsivestatus epilepticus seizures; refractory seizures; myoclonic seizures;tonic seizures; tonic-clonic seizures; simple partial seizures; complexpartial seizures; secondarily generalized seizures; atypical absenceseizures; absence seizures; atonic seizures; benign Rolandic seizures;febrile seizures; emotional seizures; focal seizures; gelastic seizures;generalized onset seizures; infantile spasms; Jacksonian seizures;massive bilateral myoclonus seizures; multifocal seizures; neonatalonset seizures; nocturnal seizures; occipital lobe seizures; posttraumatic seizures; subtle seizures; Sylvan seizures; visual reflexseizures; or withdrawal seizures. In some embodiments, the seizure is ageneralized seizure associated with Dravet Syndrome, Lennox-GastautSyndrome, Tuberous Sclerosis Complex, Rett Syndrome or PCDH19 FemalePediatric Epilepsy.

Movement Disorders

Also described herein are methods for treating a movement disorder. Asused herein, “movement disorders” refers to a variety of diseases anddisorders that are associated with hyperkinetic movement disorders andrelated abnormalities in muscle control. Exemplary movement disordersinclude, but are not limited to, Parkinson's disease and parkinsonism(defined particularly by bradykinesia), dystonia, chorea andHuntington's disease, ataxia, tremor (e.g., essential tremor), myoclonusand startle, tics and Tourette syndrome, Restless legs syndrome, stiffperson syndrome, and gait disorders.

Tremor

The methods described herein can be used to treat tremor, for examplethe compound 25 of Formula (I-I), (I-II), (I-III), (I-IV), (II-I),(II-II), or (II-III) can be used to treat cerebellar tremor or intentiontremor, dystonic tremor, essential tremor, orthostatic tremor,parkinsonian tremor, physiological tremor, psychogenic tremor, or rubraltremor. Tremor includes hereditary, degenerative, and idiopathicdisorders such as Wilson's disease, Parkinson's disease, and essentialtremor, respectively; metabolic diseases (e.g., thyroid-parathyroid-,liver disease and hypoglycemia); peripheral neuropathies (associatedwith Charcot-Marie-Tooth, Roussy-Levy, diabetes mellitus, complexregional pain syndrome); toxins (nicotine, mercury, lead, CO, Manganese,arsenic, toluene); drug-induced (narcoleptics, tricyclics, lithium,cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine,steroids, valproate, amiodarone, thyroid hormones, vincristine); andpsychogenic disorders. Clinical tremor can be classified intophysiologic tremor, enhanced physiologic tremor, essential tremorsyndromes (including classical essential tremor, primary orthostatictremor, and task- and position-specific tremor), dystonic tremor,parkinsonian tremor, cerebellar tremor, Holmes' tremor (i.e., rubraltremor), palatal tremor, neuropathic tremor, toxic or drug-inducedtremor, and psychogenic tremor.

Tremor is an involuntary, at times rhythmic, muscle contraction andrelaxation that can involve oscillations or twitching of one or morebody parts (e.g., hands, arms, eyes, face, head, vocal folds, trunk,legs).

Cerebellar tremor or intention tremor is a slow, broad tremor of theextremities that occurs after a purposeful movement. Cerebellar tremoris caused by lesions in or damage to the cerebellum resulting from,e.g., tumor, stroke, disease (e.g., multiple sclerosis, an inheriteddegenerative disorder).

Dystonic tremor occurs in individuals affected by dystonia, a movementdisorder in which sustained involuntary muscle contractions causetwisting and repetitive motions and/or painful and abnormal postures orpositions. Dystonic tremor may affect any muscle in the body. Dystonictremor occurs irregularly and often can be relieved by complete rest.

Essential tremor or benign essential tremor is the most common type oftremor. Essential tremor may be mild and nonprogressive in some, and maybe slowly progressive, starting on one side of the body but affect bothsides within 3 years. The hands are most often affected, but the head,voice, tongue, legs, and trunk may also be involved. Tremor frequencymay decrease as the person ages, but severity may increase. Heightenedemotion, stress, fever, physical exhaustion, or low blood sugar maytrigger tremors and/or increase their severity. Symptoms generallyevolve over time and can be both visible and persistent following onset.

Orthostatic tremor is characterized by fast (e.g., greater than 12 Hz)rhythmic muscle contractions that occurs in the legs and trunkimmediately after standing. Cramps are felt in the thighs and legs andthe patient may shake uncontrollably when asked to stand in one spot.Orthostatic tremor may occurs in patients with essential tremor.

Parkinsonian tremor is caused by damage to structures within the brainthat control movement. Parkinsonian tremor is often a precursor toParkinson's disease and is typically seen as a “pill-rolling” action ofthe hands that may also affect the chin, lips, legs, and trunk. Onset ofparkinsonian tremor typically begins after age 60. Movement starts inone limb or on one side of the body and can progress to include theother side.

Physiological tremor can occur in normal individuals and have noclinical significance. It can be seen in all voluntary muscle groups.Physiological tremor can be caused by certain drugs, alcohol withdrawal,or medical conditions including an overactive thyroid and hypoglycemia.The tremor classically has a frequency of about 10 Hz.

Psychogenic tremor or hysterical tremor can occur at rest or duringpostural or kinetic movement. Patient with psychogenic tremor may have aconversion disorder or another psychiatric disease.

Rubral tremor is characterized by coarse slow tremor which can bepresent at rest, at posture, and with intention. The tremor isassociated with conditions that affect the red nucleus in the midbrain,classical unusual strokes.

Parkinson's Disease affects nerve cells in the brain that producedopamine. Symptoms include muscle rigidity, tremors, and changes inspeech and gait. Parkinsonism is characterized by tremor, bradykinesia,rigidity, and postural instability. Parkinsonism shares symptoms foundin Parkinson's Disease, but is a symptom complex rather than aprogressive neurodegenerative disease.

Dystonia is a movement disorder characterized by sustained orintermittent muscle contractions causing abnormal, often repetitivemovements or postures. Dystonic movements can be patterned, twisting,and may be tremulous. Dystonia is often initiated or worsened byvoluntary action and associated with overflow muscle activation.

Chorea is a neurological disorder characterized by jerky involuntarymovements typically affecting the shoulders, hips, and face.Huntington's Disease is an inherited disease that causes nerve cells inthe brain to waste away. Symptoms include uncontrolled movements,clumsiness, and balance problems. Huntington's disease can hinder walk,talk, and swallowing.

Ataxia refers to the loss of full control of bodily movements, and mayaffect the fingers, hands, arms, legs, body, speech, and eye movements.

Myloclonus and Startle is a response to a sudden and unexpectedstimulus, which can be acoustic, tactile, visual, or vestibular.

Tics are an involuntary movement usually onset suddenly, brief,repetitive, but non-rhythmical, typically imitating normal behavior andoften occurring out of a background of normal activity. Tics can beclassified as motor or vocal, motor tics associated with movements whilevocal tics associated with sound. Tics can be characterized as simple orcomplex. For example simple motor tics involve only a few musclesrestricted to a specific body part. Tourette Syndrome is an inheritedneuropsychiatric disorder with onset in childhood, characterized bymultiple motor tics and at least one vocal tic.

Restless Legs Syndrome is a neurologic sensorimotor disordercharacterized by an overwhelming urge to move the legs when at rest.

Stiff Person Syndrome is a progressive movement disorder characterizedby involuntary painful spasms and rigidity of muscles, usually involvingthe lower back and legs. Stiff-legged gait with exaggerated lumbarhyperlordosis typically results. Characteristic abnormality on EMGrecordings with continuous motor unit activity of the paraspinal axialmuscles is typically observed. Variants include “stiff-limb syndrome”producing focal stiffness typically affecting distal legs and feet.

Gait disorders refer to an abnormality in the manner or style ofwalking, which results from neuromuscular, arthritic, or other bodychanges. Gait is classified according to the system responsible forabnormal locomotion, and include hemiplegic gait, diplegic gait,neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait,ataxic gait, and sensory gait.

Anesthesia Sedation

Anesthesia is a pharmacologically induced and reversible state ofamnesia, analgesia, loss of responsiveness, loss of skeletal musclereflexes, decreased stress response, or all of these simultaneously.These effects can be obtained from a single drug which alone providesthe correct combination of effects, or occasionally with a combinationof drugs (e.g., hypnotics, sedatives, paralytics, analgesics) to achievevery specific combinations of results. Anesthesia allows patients toundergo surgery and other procedures without the distress and pain theywould otherwise experience.

Sedation is the reduction of irritability or agitation by administrationof a pharmacological agent, generally to facilitate a medical procedureor diagnostic procedure.

Sedation and analgesia include a continuum of states of consciousnessranging from minimal sedation (anxiolysis) to general anesthesia.

Minimal sedation is also known as anxiolysis. Minimal sedation is adrug-induced state during which the patient responds normally to verbalcommands. Cognitive function and coordination may be impaired.Ventilatory and cardiovascular functions are typically unaffected.

Moderate sedation/analgesia (conscious sedation) is a drug-induceddepression of consciousness during which the patient respondspurposefully to verbal command, either alone or accompanied by lighttactile stimulation. No interventions are usually necessary to maintaina patent airway. Spontaneous ventilation is typically adequate.Cardiovascular function is usually maintained.

Deep sedation/analgesia is a drug-induced depression of consciousnessduring which the patient cannot be easily aroused, but respondspurposefully (not a reflex withdrawal from a painful stimulus) followingrepeated or painful stimulation. Independent ventilatory function may beimpaired and the patient may require assistance to maintain a patentairway. Spontaneous ventilation may be inadequate. Cardiovascularfunction is usually maintained.

General anesthesia is a drug-induced loss of consciousness during whichthe patient is not arousable, even to painful stimuli. The ability tomaintain independent ventilatory function is often impaired andassistance is often required to maintain a patent airway. Positivepressure ventilation may be required due to depressed spontaneousventilation or drug-induced depression of neuromuscular function.Cardiovascular function may be impaired.

Sedation in the intensive care unit (ICU) allows the depression ofpatients' awareness of the environment and reduction of their responseto external stimulation. It can play a role in the care of thecritically ill patient, and encompasses a wide spectrum of symptomcontrol that will vary between patients, and among individualsthroughout the course of their illnesses. Heavy sedation in criticalcare has been used to facilitate endotracheal tube tolerance andventilator synchronization, often with neuromuscular blocking agents.

In some embodiments, sedation (e.g., long-term sedation, continuoussedation) is induced and maintained in the ICU for a prolonged period oftime (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1month, 2 months). Long-term sedation agents may have long duration ofaction. Sedation agents in the ICU may have short elimination half-life.

Procedural sedation and analgesia, also referred to as conscioussedation, is a technique of administering sedatives or dissociativeagents with or without analgesics to induce a state that allows asubject to tolerate unpleasant procedures while maintainingcardiorespiratory function.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions, and methodsprovided herein and are not to be construed in any way as limiting theirscope.

Materials and Methods

The compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

The compounds provided herein may be isolated and purified by knownstandard procedures. Such procedures include (but are not limited to)trituration, column chromatography, HPLC, or supercritical fluidchromatography (SFC). The following schemes are presented with detailsas to the preparation of representative oxysterols that have been listedherein. The compounds provided herein may be prepared from known orcommercially available starting materials and reagents by one skilled inthe art of organic synthesis. Exemplary chiral columns available for usein the separation/purification of the enantiomers/diastereomers providedherein include, but are not limited to, CHRALPAK® AD-10, CHIRALCEL® OB,CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® 30 OD-H, CHIRALCEL® OF,CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

¹H-NMR reported herein (e.g., for the region between δ (ppm) of about0.5 to about 4 ppm) will be understood to be an exemplary interpretationof the NMR spectrum (e.g., exemplary peak integratations) of a compound.

Exemplary general method for preparative HPLC: Column: Waters RBridgeprep 10 μm C18, 19*250 mm. Mobile phase: acetonitrile, water (NH₄HCO₃)(30 L water, 24 g NH₄HCO₃, 30 mL NH₃·H₂O). Flow rate: 25 mL/min.

Exemplary general method for analytical HPLC: Mobile phase: A: water (10mM NH₄HCO₃), B: acetonitrile Gradient: 5%-95% B in 1.6 or 2 min Flowrate: 1.8 or 2 mL/min; Column: XBridge C18, 4.6*50 mm, 3.5 μm at 45° C.

LC-ELSD/MS Mobile Phase: 1.5 mL/4 L TFA in water (solvent A) and 0.75mL/4 L TFA in acetonitrile (solvent B), using the elution gradient10%-80% (solvent B) over 0.9 minutes and holding at 80% for 0.6 minutesat a flow rate of 1.2 mL/min; Column: Xtimate C18 2.1*30 mm, 3 μm;Column temperature: 50° C.; PDA, wavelength: UV 220 nm; MS ionization:ESI;& ELSD.

Exemplary general method for SFC: Column: CHIRALPAK® AD CSP (250 mm*30mm, 10 m), Gradient: 45% B, A=NH₃H₂O, B=MeOH, flow rate: 60 mL/min. Forexample, AD_3_EtOH_DEA_5_40_25ML would indicate: “Column: Chiralpak AD-3150×4.6 mm I.D., 3 μm Mobile phase: A: CO2 B:ethanol (0.05% DEA)Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5%of B for 2.5 min Flow rate: 2.5 mL/min Column temp: 35° C.”.

Formula (II-I), (II-II), or (II-III) Abbreviations

Abbreviations: PE: petroleum ether; EtOAc: ethyl acetate; THF:tetrahydrofuran; PCC: pyridinium chlorochromate; TLC: thin layerchromatography; t-BuOK: potassium tert-butoxide; 9-BBN:9-borabicyclo[3.3.1]nonane; Pd(t-Bu₃P)₂:bis(tri-tert-butylphosphine)palladium(0); AcCl: acetyl chloride;i-PrMgCl: Isopropylmagnesium chloride; TBSCl:tert-Butyl(chloro)dimethylsilane; (i-PrO)₄Ti: titaniumtetraisopropoxide; BHT: 2,6-di-t-butyl-4-methylphenoxide; Me: methyl;i-Pr: iso-propyl; t-Bu: tert-butyl; Ph: phenyl; Et: ethyl; Bz: benzoyl;BzCl: benzoyl chloride; CsF: cesium fluoride; DCC:dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP:4-dimethylaminopyridine; DMP: Dess-Martin periodinane; EtMgBr:ethylmagnesium bromide; EtOAc: ethyl acetate; TEA: triethylamine; AlaOH:alanine; Boc: t-butoxycarbonyl. Py: pyridine; TBAF:tetra-n-butylammonium fluoride; TBS: t-butyldimethylsilyl; TMS:trimethylsilyl; TMSCF₃: (Trifluoromethyl)trimethylsilane; Ts:p-toluenesulfonyl; Bu: butyl; Ti(OiPr)₄: tetraisopropoxytitanium; LAH:Lithium Aluminium Hydride; LDA: lithium diisopropylamide; LiOH·H₂O:lithium hydroxide hydrates; MAD: methyl aluminumbis(2,6-di-t-butyl-4-methylphenoxide); MeCN: acetonitrile; NBS:N-bromosuccinimide; Na₂SO₄: sodium sulfate; Na₂S₂O₃: sodium thiosulfate;MeCN: acetonitrile; MeOH: methanol; Boc: t-butoxycarbonyl; MTBE: methyltert-butyl ether; K-selectride: Potassium tri(s-butyl)borohydride;DIBAL-H: diisobutylaluminum hydride; HATU:O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; m-CPBA: meta chloroperbenzoic acid.

Example I-1: Synthesis of1-((1S,3aS,3bR,5aS,7R,9aR,9bS,11aS)-7-hydroxy-7,11a-dimethylhexadecahydroindeno[4,5-c]chromen-1-yl)ethan-1-one(I-A15)

Synthesis of I-A2

To a suspension of I-A1 (reported in reference Tetrahedron, 2006,4384-4392) (70 g, 0.25 mol) in THF (1.5 L) was added NaH (40.3 g, 60%,1.0 mol) and BnBr (173 g, 1.0 mol) at 20° C. The mixture was stirred at40° C. for 40 h. The mixture was quenched by aq. NH₄Cl (200 mL). Themixture was concentrated to remove THF. The residue was extracted withPE/EtOAc (10:1, 500 mL). The organic layer was separated, dried overNa₂SO₄, filtered and concentrated in vacuum to give the material (170g). The material was purified by flash column (0˜10% EtOAc in PE) togive I-A2 as a solid.

Synthesis of I-A3

To a solution of I-A2 (65 g, 0.14 mol) in TH (650 mL) was added BH₃.Me₂S(42.6 mL, 10 M, 0.42 mol) and the mixture was stirred at 15° C. for 16h. To the mixture was added EtOH (65.4 g, 1.42 mol) dropwise followed byNaOH (283 mL, 5 M) and H₂O₂(141 mL, 10 M). The mixture was stirred at60° C. for 5 h. The mixture was quenched by Na₂SO₃ (2 L, 10%) andextracted with EtOAc (1 L). The organic layer was separated, driedNa₂SO₄, filtered and concentrated in vacuum to give I-A3 (55 g) as asolid.

Synthesis of I-A4

To a solution of I-A3 (180 g, 379 mmol) in DCM (2 L) was added DMP (240g, 568 mmol) and water (6.59 g, 365 mmol). The mixture was stirred at20° C. for 0.5 h. The mixture was quenched by aq. NaHCO₃ (500 mL) andaq. Na₂S₂O₃ (500 mL). The organic layer was separated, dried overNa₂SO₄, filtered and concentrated in vacuum to give I-A4 (190 g), whichwas purified by flash column (030% EtOAc in PE) to give I-A4 (60 g) as asolid. ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.45-7.20 (m, 11H), 4.59-4.37 (m,4H), 3.40-3.30 (m, 1H), 3.28-3.20 (m, 1H), 2.45-2.20 (m, 2H), 2.11-1.83(m, 6H), 1.55-1.37 (m, 3H), 1.25-0.70 (m, 9H), 0.75 (s, 3H).

Synthesis of I-A5

To a solution of I-A4 (25 g, 52.8 mmol) in DCM (1 L) was added m-CPBA(21.2 g, 85%, 105 mmol) and TsOH (9.09 g, 52.8 mmol) and the mixture wasstirred 20° C. for 16 hrs. The mixture was quenched by Na₂SO₃ (2 L, 5%).The organic layer was separated, concentrated and purified by flashcolumn (1020% EtOAc in PE) to give I-A5 (12 g, 46.5%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ_(H) 7.40-7.20 (m, 10H), 4.65-4.45 (m, 4H),4.20-4.05 (m, 1H), 3.45-3.20 (m, 2H), 2.60-2.15 (m, 3H), 2.10-1.85 (m,4H), 1.75-1.50 (m, 5H), 1.50-1.05 (m, 6H), 0.95-0.75 (m, 5H).

Synthesis of I-A6

To a solution of I-A5 (12 g, 24.5 mmol) in toluene (240 mL) was addedDIBAL-H (73.5 mL, 1 M in toluene, 73.5 mmol). The mixture was stirred at−70° C. for 2 hrs. To the mixture was added Na₂SO₄.10H₂O (30 g) andfiltered. The filtrate was concentrated to give I-A6 (9 g, 75%) as anoil.

¹H NMR (400 MHz, CDCl₃) δ_(H) 7.40-7.20 (m, 10H), 5.15-5.00 (m, 1H),4.60-4.45 (m, 4H), 3.85-3.70 (m, 1H), 3.45-3.30 (m, 2H), 2.68 (br, 1H),2.10-1.80 (m, 7H), 1.70-1.50 (m, 2H), 1.45-1.00 (m, 10H), 0.85 (s, 3H),0.80-0.60 (m, 1H).

Synthesis of I-A7

To a solution of I-A6 (9 g, 18.3 mmol) in toluene (900 mL) was addedcelite (9 g), pyridine (27 mL), HgO (11.8 g, 54.9 mmol) and I₂ (13.9 g,54.9 mmol) at 20° C. to give a suspension. The mixture was irradiated byhigh-pressure mercury lamp for 2 h with being cooled by flowing water tomaintaining inner temperature between 20˜25° C. to give a suspension.The mixture filtered, concentrated and purified by flash column (0˜30%EtOAc in PE) to give I-A7 (7 g) as an oil.

¹H NMR (400 MHz, CDCl₃) δ_(H) 8.10 (s, 1H), 7.40-7.20 (m, 10H), 4.88(dt, 1H), 4.60-4.45 (m, 4H), 3.50-3.35 (m, 2H), 3.31 (dd, 1H), 3.20 (dd,1H), 2.55-2.54 (m, 1H), 2.20-2.00 (m, 2H), 1.92-1.83 (m, 1H), 1.70-1.55(m, 5H), 1.50-1.10 (m, 8H), 0.84 (s, 3H), 0.80-0.70 (s, 1H).

Synthesis of I-A8

To a solution of I-A7 (6.1 g, 9.9 mmol) in THE (60 mL) and MeOH (60 mL)was added K₂CO3 (6.92 g, 49.4 mmol). The mixture was stirred at 20° C.for 1 h. To the mixture was added water (200 mL) and extracted withEtOAc (300 mL). The organic layer was separated, dried over Na₂SO₄,filtered and concentrated in vacuum to give 6 g as an oil. The product(6 g) was combined with another batch of product (1.1 g) and purified byflash column (10˜15% EtOAc in PE) to give I-A8 (5.7 g, 72%) as an oil.

¹H NMR (400 MHz, CDCl₃) δ_(H) 7.40-7.20 (m, 10H), 4.60-4.45 (m, 4H),3.55-3.35 (m, 2H), 3.35-3.25 (m, 1H), 3.25-3.15 (m, 1H), 2.55-2.45 (m,1H), 2.15-2.00 (m, 2H), 1.95-1.85 (m, 1H), 1.75-1.45 (m, 6H), 1.45-1.05(m, 9H), 0.85 (s, 3H), 0.80-0.70 (m, 1H).

Synthesis of I-A9

To a solution of I-A8 (5.7 g, 9.7 mmol) in THE (90 mL) was added NaH(3.86 g, 60%, 97 mmol). The mixture was stirred at 20° C. for 4 h. Themixture was quenched by water (100 mL) and extracted with PE (200 mL).The organic layer was separated, concentrated and purified by flashcolumn (0˜10% EtOAc in PE) to give I-A9 (3.7 g, 83%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ_(H) 7.40-7.20 (m, 10H), 4.60-4.45 (m, 4H),3.85 (dd, 1H), 3.45-3.30 (m, 2H), 3.07 (t, 1H), 2.95-2.70 (m, 1H),2.40-2.30 (m, 1H), 2.10-1.85 (m, 4H), 1.75-1.70 (m, 1H), 1.55-0.95 (m,10H), 0.87 (s, 3H), 0.80-0.70 (m, 2H).

Synthesis of I-A10

To a solution of I-A9 (4 g, 8.7 mmol) in THF (50 mL) was added Pd(OH)₂/C(dry, 10%, 1 g) under N₂. The suspension was degassed under vacuum andpurged with H₂ for three times. The mixture was stirred under H₂ (45psi) at 40° C. for 16 hours to give a suspension. The reaction mixturewas filtered through a pad of Celite and washed with THE (3×10 mL). Thefiltrate was concentrated and purified by flash column (25˜90% EtOAc inPE) to give I-A10 (1.4 g, 58%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ_(H) 3.85 (dd, 1H), 3.75-3.60 (m, 2H), 3.09 (t,1H), 3.00-2.85 (m, 1H), 2.30-2.20 (m, 1H), 2.10-1.70 (m, 5H), 1.60-0.90(m, 12H), 0.85-0.70 (m, 5H); LC-ELSD/MS purity 99%, MS ESI calcd. forC₁₇H₂₇O₂ [M+H-H₂O]⁺ 263.2, found 263.2.

Synthesis of I-A11

To a solution of I-A10 (1.38 g, 4.9 mmol) in DCM (80 mL) was added DMP(8.31 g, 19.6 mmol) at 25° C. and inner temperature was raised to 30° C.The mixture was stirred at 30° C. for 1 h. The mixture was washed with amixed solution of NaHCO₃ (200 mL, sat.) and Na₂S₂O₃ (200 mL, sat.)twice, dried over Na₂SO₄, filtered, concentrated in vacuum and purifiedby flash column (15˜35% EtOAc in PE) to give I-A1 (1.3 g, 96%) as asolid.

¹H NMR (400 MHz, CDCl₃) δ_(H) 4.01 (dd, 1H), 3.32-3.17 (m, 2H), 2.70(ddd, 1H), 2.52-2.36 (m, 3H), 2.32-2.21 (m, 1H), 2.18-2.03 (m, 2H),1.94-1.80 (m, 3H), 1.74 (dq, 1H), 1.66-1.53 (m, 1H), 1.51-1.41 (m, 1H),1.40-1.21 (m, 3H), 1.13 (dq, 1H), 1.04-0.96 (m, 1H), 0.94 (s, 3H);LC-ELSD/MS purity 99%, MS ESI calcd. for C₁₇H₂₅O₃ [M+H]⁺ 277.2, found277.1.

Synthesis of I-A12

A suspension of LiCl (1.58 g, 37.4 mmol, anhydrous) in THE (100 mL,anhydrous) was stirred at 20° C. for 30 mins under N₂. FeCl₃ (3.13 g,19.3 mmol, anhydrous) was added at 20° C. The mixture was cooled to −30°C. To the mixture was added MeMgBr (24.1 mL, 3M in diethyl ether, 72.4mmol) dropwise at −30° C. The mixture was stirred at −30° C. for 10mins. A solution of I-A11 (1.67 g, 6.0 mmol) in TH (10 mL) was added at−30° C. The mixture was stirred at −15° C. for 2 hours. To the mixturewas added citric acid (100 mL, 15% aq.). The mixture was extracted withEtOAc (200 mL). The combined organic phase was dried over anhydrousNa₂SO₄, filtered, concentrated to give I-A12 (1.7 g, 96%) as a solid.The product (50 mg) was triturated from EtOAc (1 mL) to give I-A12 (21mg) as a solid.

¹H NMR (400 MHz, CDCl₃) δ_(H) 3.97 (dd, 1H), 3.38-3.30 (m, 1H), 3.97 (t,1H), 2.44 (dd, 1H), 2.44 (td, 1H), 1.93-1.79 (m, 4H), 1.77-1.60 (m, 4H),1.43-1.10 (m, 10H), 1.06-0.92 (m, 2H), 0.87 (s, 3H); LC-ELSD/MS purity99%, MS ESI calcd. for C₁₈H₂₇O₂ [M+H-H₂O]⁺ 275.2, found 275.1.

Synthesis of I-A13

To a mixture of MePPh₃Br (6.27 g, 16.9 mmol) in THE (20 mL) was addedt-BuOK (1.89 g, 16.9 mol) at 25° C. under N₂. The resulting mixture wasstirred at 40° C. for 30 min. A solution of I-A12 (1.65 g, 5.6 mmol) inTHE (5 mL) was added at 40° C. The reaction mixture was stirred at 40°C. for 1 hour to give a suspension. The reaction mixture was quenchedwith 10% NH₄Cl aqueous (20 mL) and extracted with EtOAc (40 mL). Theorganic phase was concentrated in vacuum and purified by flash column(5˜20% EtOAc in PE) to give I-A13 (1.4 g, 82%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ_(H) 5.12 (tq, 1H), 3.89 (dd, 1H), 3.31 (ddd,1H), 3.18 (t, 1H), 2.42-2.33 (m, 1H), 2.31-2.23 (m, 1H), 2.23-2.11 (m,1H), 1.88 (ddd, 1H), 1.84-1.70, (m, 2H), 1.65 (td, 3H), 1.65-1.46 (m,5H), 1.42-1.30 (m, 2H), 1.26 (s, 3H), 1.25-1.12 (m, 4H), 1.03-0.92 (m,2H), 0.90 (s, 3H); LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₀H₃₁O[M+H-H₂O]⁺ 287.2, found 287.2.

Synthesis of I-A14

A solution of I-A13 (1.38 g, 4.5 mmol) in THE (20 mL) in 9-BBN dimer(3.29 g, 13.5 mmol) was stirred at 40° C. for 16 hours. To the resultingmixture was added ethanol (2.08 g, 45.3 mmol) at 15° C., followed byNaOH aqueous (9.06 mL, 5.0 M, 45.3 mmol) at 15° C. Hydrogen peroxide(4.53 mL, 10 M, 45.3 mmol) was added drop-wise at 0° C. The reactionmixture was stirred at 60° C. for 1 hour. The mixture was cooled to 15°C. The mixture was quenched by Na₂SO₃ (20 mL, 10%), extracted with EtOAc(2×20 mL). The combined organic layer was dried over Na₂SO₄, filtered,concentrated and purified by flash column (30˜60% EtOAc in PE) to giveI-A14 (1.45 g, 99%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ_(H) 3.85 (dd, 1H), 3.80-3.65 (m, 1H),3.90-3.75 (m, 1H), 3.16 (t, 1H), 2.00-1.85 (m, 3H), 1.80-1.70 (m, 2H),1.70-1.60 (m, 2H), 1.55-1.30 (m, 5H), 1.26 (s, 3H), 1.23 (d, 3H),1.15-0.90 (m, 9H), 0.70 (s, 3H); LC-ELSD/MS purity 99%, MS ESI calcd.for C₂₀H₃₃O₂ [M+H-H₂O]⁺ 305.2, found 305.2.

Synthesis of I-A15

To a solution of I-A14 (1.43 g, 4.4 mmol) in DCM (30 mL) was added DMP(3.75 g, 8.8 mmol) at 25° C. and inner temperature was raised to 30° C.The mixture was stirred at 30° C. for 1 h. The mixture was washed with amixed solution of NaHCO₃ (100 mL, sat.) and Na₂S₂O₃ (100 mL, sat.)twice, dried over Na₂SO₄, filtered, concentrated in vacuum andtriturated in MeCN (20 mL) to give I-A15 (1.12 g, 79%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ_(H) 3.85 (dd, 1H), 3.31 (ddd, 1H), 3.16 (t,1H), 2.52 (t, 1H), 2.24-2.14 (m, 1H), 2.12 (s, 3H), 2.07-2.00 (m, 1H),1.92-1.60 (m, 5H), 1.57-1.30 (m, 5H), 1.26 (s, 3H), 1.25-1.10 (m, 4H),1.06 (br, 1H), 1.12-0.87 (m, 2H), 0.65 (s, 3H); LC-ELSD/MS purity 99%,MS ESI calcd. for C₂₀H₃₁O₂ [M+H-H₂O]⁺ 303.2, found 303.2.

Example I-2: Synthesis of1-(2-((1S,3aS,3bR,5aS,7R,9aR,9bS,1aS)-7-hydroxy-7,11a-dimethylhexadecahydroindeno[4,5-c]chromen-1-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile(I-A17)

Synthesis of I-A16

To a solution of I-A15 (150 mg, 0.5 mmol) in MeOH (2 mL) was added HBr(18.9 mg, 0.1 mmol, 40% in water) and Br₂ (74.7 mg, 0.5 mmol) at 25° C.The mixture was stirred at 25° C. for 3 hrs. The mixture was poured intoNaHCO₃ (20 mL, saturated), extracted with EtOAc (2×20 mL). The organiclayer was separated, dried over Na₂SO₄, filtered and concentrated invacuum to give I-A16 (170 mg) as a solid.

¹H NMR (400 MHz, CDCl₃) δ_(H) 3.95-3.89 (m, 2H), 3.85 (dd, 1H),3.39-3.25 (m, 1H), 3.16 (t, 1H), 2.82 (t, 1H), 2.26-2.13 (m, 1H),1.98-1.69 (m, 5H), 1.67-1.61 (m, 3H), 1.53-1.43 (m, 2H), 1.42-1.29 (m,3H), 1.27 (s, 3H), 1.24-1.15 (m, 3H), 1.02-0.90 (m, 2H), 0.68 (s, 3H).

Synthesis of I-A17

To a solution of I-A16 (170 mg, 0.4 mmol) in acetone (3 mL) was added1H-pyrazole-4-carbonitrile (59.4 mg, 0.6 mmol) and K₂CO3 (175 mg, 1.3mmol). The mixture was stirred at 25° C. for 16 hrs. To the mixture wasadded water (20 mL) and the mixture was extracted with EtOAc (2×20 mL).The organic layer was separated, concentrated and purified by flashcolumn (30˜80% EtOAc in PE) to give I-A17 (100 mg, 52% above two steps)as a solid.

¹H NMR (400 MHz, CDCl₃) δ_(H) 7.86 (s, 1H), 7.81 (s, 1H), 5.06-4.86 (m,2H), 3.90-3.82 (m, 1H), 3.37-3.29 (m, 1H), 3.17 (t, 1H), 2.59 (t, 1H),2.29-2.17 (m, 1H), 2.11-2.04 (m, 1H), 1.92-1.70 (m, 4H), 1.68-1.61 (m,2H), 1.55-1.47 (m, 2H), 1.44-1.28 (m, 3H), 1.28-1.18 (m, 6H), 1.04-0.81(m, 3H), 0.71 (s, 3H); LC-ELSD/MS purity 99%, MS ESI calcd. forC₂₄H₃₄N₃O₃ [M+H]⁺ 412.2, found 412.2.

Formula (II-I), (II-II), and (II-III) Abbreviations

Abbreviations: PE: petroleum ether; EtOAc: ethyl acetate; THF:tetrahydrofuran; PCC: pyridinium chlorochromate; TLC: thin layerchromatography; t-BuOK: potassium tert-butoxide; 9-BBN:9-borabicyclo[3.3.1]nonane; Pd(t-Bu₃P)₂:bis(tri-tert-butylphosphine)palladium(O); AcCl: acetyl chloride;i-PrMgCl: Isopropylmagnesium chloride; TBSCl:tert-Butyl(chloro)dimethylsilane; (i-PrO)₄Ti: titaniumtetraisopropoxide; BHT: 2,6-di-t-butyl-4-methylphenoxide; Me: methyl;i-Pr: iso-propyl; t-Bu: tert-butyl; Ph: phenyl; Et: ethyl; Bz: benzoyl;BzCl: benzoyl chloride; CsF: cesium fluoride; DCC:dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP:4-dimethylaminopyridine; DMP: Dess-Martin periodinane; EtMgBr:ethylmagnesium bromide; EtOAc: ethyl acetate; TEA: triethylamine; AlaOH:alanine; Boc: t-butoxycarbonyl. Py: pyridine; TBAF:tetra-n-butylammonium fluoride; THF: tetrahydrofuran; TBS:t-butyldimethylsilyl; TMS: trimethylsilyl; TMSCF₃:(Trifluoromethyl)trimethylsilane; Ts: p-toluenesulfonyl; Bu: butyl;Ti(OiPr)₄: tetraisopropoxytitanium; LAH: Lithium Aluminium Hydride; LDA:lithium diisopropylamide; LiOH·H₂O: lithium hydroxide hydrates; MAD:methyl aluminum bis(2,6-di-t-butyl-4-methylphenoxide); MeCN:acetonitrile; NBS: N-bromosuccinimide; Na₂SO₄: sodium sulfate; Na₂S₂O₃:sodium thiosulfate; MeCN: acetonitrile; MeOH: methanol; Boc:t-butoxycarbonyl; MTBE: methyl tert-butyl ether; K-selectride: Potassiumtri(s-butyl)borohydride.

Example II-1: Synthesis of1-((1S,3aS,3bR,5aR,7R,9aS,9bR,11aS)-7-hydroxy-7,11a-dimethylhexadecahydrophenanthro[1,2-c]furan-1-yl)ethan-1-one(II-A11b)

Synthesis of II-A2

To a solution of i-Pr2NH (13.8 g, 137 mmol) in THE (100 mL) was addedBuLi (54.8 mL, 2.5 M, 137 mmol) at −70° C. The mixture was warmed to 0°C. and stirred at 0° C. for 10 min. To the mixture was added a solutionof II-A1 (reported in patent WO2014/169833) (10 g, 34.4 mmol) in THE(100 mL) at −70° C. The mixture was stirred at −70° C. for 1 h. To themixture was added TMSCl (11.1 g, 103 mmol). The mixture was stirred at−70° C. for 1 h and 0° C. for 15 min. The mixture was quenched by NH₄Cl(100 mL, sat.) and extracted with EtOAc (200 mL). The organic layer wasseparated, dried over Na2SO4, filtered and concentrated in vacuum togive II-A2 (16.2 g) as an oil.

¹H NMR (400 MHz, CDCl₃) δ_(H) 4.52-4.45 (m, 1H), 2.04-1.95 (m, 1H),1.90-1.55 (m, 7H), 1.50-1.35 (m, 6H), 1.35-1.20 (m, 7H), 1.20-1.00 (m,4H), 0.82 (s, 3H), 0.19 (s, 9H).

Synthesis of II-A3

To a solution of II-A2 (16.2 g, 44.6 mmol) in DCM (240 mL) andAcetonitrile (80 mL) was added Pd(OAc)₂ (10 g, 44.6 mmol). The mixturewas stirred at 15° C. for 16 h. The reaction mixture was filteredthrough a pad of celite and washed with DCM (100 mL). The combinedorganic filtrate was washed with a mixed solution of Na2EDTA (15 g) andNa2CO3 (10 g) in water (200 mL), dried over Na2SO4, filteredconcentrated in vacuum and purified by flash column (1550% EtOAc in PE)to give II-A3 (9 g, 90% above 2 steps) as a solid.

¹H NMR (400 MHz, CDCl3) δ_(H) 7.52 (dd, J=0.8, 6.0 Hz, 1H), 6.02 (dd,J=3.2, 6.0 Hz, 1H), 2.43-2.41 (m, 1H), 1.96-1.61 (m, 8H), 1.59-1.26 (m,13H), 1.26-1.19 (m, 1H), 1.07 (s, 3H); LC-ELSD purity 99%, MS ESI calcd.for C19H27O [M+H-H2O]+ 271.2, found 271.2.

Synthesis of II-A4

To a solution of II-A3 (7.5 g, 26.0 mmol) in MeOH (150 mL) and THE (30mL) was added CeCl₃.7H₂O (10.6 g, 28.6 mmol) and Me₂S (400 mg, 6.4mmol). The mixture was stirred for 1 h at 15° C. NaBH₄ (983 mg, 26.0mmol) was added in small portions maintaining a temperature at −5° C.The mixture was stirred for 10 min at 0° C. The mixture was quenched byNH₄Cl (50 mL, sat.), diluted with water (300 mL) and filtered. The solidwas washed with water (3×50 mL) and dried in vacuum to give II-A4 (7.3g, 97%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ_(H) 5.91 (d, J=5.6 Hz, 1H), 5.72-5.56 (m, 1H),4.38-4.26 (m, 1H), 1.92-1.80 (m, 5H), 1.74-1.60 (m, 3H), 1.55-1.28 (m,13H), 1.25-1.07 (m, 3H), 0.82 (s, 3H); LC-ELSD purity 99%, MS ESI calcd.for C₁₉H₂₈ [M+H-2H₂O]⁺ 255.2, found 255.3.

Synthesis of II-A5

To a suspension of II-A4 (7.7 g, 26.5 mmol) in DCM (100 mL) was added im(5.41 g, 79.5 mmol) and TBSCl (5.98 g, 39.7 mmol). The mixture wasstirred at 15° C. for 1 h. To the mixture was added water (100 mL) andfiltered. The organic layer was separated, dried over Na₂SO₄, filtered,concentrated in vacuum and purified by flash column (0-15% EtOAc in PE)to give II-A5 (10.8 g, 100%) as an oil.

¹H NMR (400 MHz, CDCl₃) δ_(H) 5.88-5.78 (m, 1H), 5.62-5.52 (m, 1H),4.30-4.25 (m, 1H), 1.90-1.60 (m, 7H), 1.55-1.35 (m, 8H), 1.35-1.20 (m,6H), 1.20-1.05 (m, 2H), 0.90 (s, 9H), 0.78 (s, 3H), 0.15-0.00 (m, 6H).

Synthesis of II-A6

To a solution of II-A5 (8.8 g, 21.7 mmol) in DCM (200 mL) and MeOH (200mL) was added NaHCO₃ (8.8 g, 104 mmol). To the mixture was passed ozone(1 atm) at −70° C. until the mixture was turned blue (ca. 10 min). O₂was passed through the solution for an additional 5 mins. To the mixturewas added NaBH₄ (3.28 g, 86.8 mmol) at −70° C. in portions and thesolution was allowed to warmed to 0° C. over 1 h. The mixture wasquenched by NH₄Cl (200 mL, sat., aq.) and extracted with DCM (200 mL).The combined organic layer was dried over Na₂SO₄, filtered, concentratedin vacuum to give 10 g lactol intermediate as a foaming-like solid.

To a solution of the lactol intermediate (10 g) in THE (50 mL) andi-PrOH (50 mL) was added NaBH₄ (4 g, 106 mmol). The mixture was stirredat 70° C. for 20 h. The mixture was quenched by NH₄Cl (200 mL, sat.) andconcentrated to remove most organic solvent. The residue was extractedwith EtOAc (2×100 mL). The combined organic layer was dried over Na₂SO₄,filtered and concentrated and purified by flash column (25˜50% EtOAc inPE) to give II-A6 (7.2 g, 75%) as an oil.

¹H NMR (400 MHz, CDCl₃) δ_(H) 3.80-3.55 (m, 5H), 3.15-2.85 (br, 1H),2.70-2.40 (br, 1H), 1.90-1.50 (m, 11H), 1.45-1.05 (m, 12H), 1.00-0.85(m, 12H), 0.09 (s, 6H).

Synthesis of II-A7a & II-A7b

To a solution of II-A6 (5.6 g, 12.7 mmol) in THE (60 mL) was added BuLi(5.6 mL, 2.5 M in hexane, 14 mmol) at 0° C. and stirred for 10 min. Tothe mixture was added TsCl (2.64 g, 13.9 mmol) in THE (30 mL) at 0° C.and stirred for 10 min. To the mixture was added another batch of BuLi(5.6 mL, 2.5 M in hexane, 14 mmol) at 0° C. and stirred for 30 min. Tothe mixture was added TsCl (500 mg) in THE (10 mL) at 0° C. and stirredfor 10 min. Another batch of BuLi (5.6 mL, 2.5 M in hexane, 14 mmol) wasadded at 0° C. and stirred for 30 min. Another batch of BuLi (5.6 mL,2.5 M in hexane, 14 mmol) was added at 30° C. and stirred for 1 h. Themixture was quenched by water (50 mL) and extracted with EtOAc (200 mL).The organic layer was separated, dried over Na₂SO₄, filtered andconcentrated in vacuum and purified by flash column (0˜50% EtOAc in PE)to give II-A7a (2.8 g, 44%) and II-A7b (1.7 g, 27%,) both as oils. Theepimers were assigned by HMBC.

II-A7a: ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.84 (t, J=7.6 Hz, 1H), 3.63-3.55(m, 2H), 3.48 (dt, J=6.4, 8.8 Hz, 1H), 3.40 (dd, J=7.6, 12.0 Hz, 1H),1.90-1.60 (m, 7H), 1.50-1.30 (m, 8H), 1.30-1.00 (m, 8H), 0.97 (s, 3H),0.89 (s, 9H), 0.05 (s, 6H).

II-A7b: ¹H NMR (400 MHz, CDCl₃) δ_(H) 3.86 (t, J=7.6 Hz, 1H), 3.72 (dd,J=6.0, 10.0 Hz, 1H), 3.63 (dd, J=6.8, 10.0 Hz, 1H), 3.46 (t, J=6.4 Hz,1H), 3.39 (dd, J=7.6, 12.0 Hz, 1H), 1.90-1.60 (m, 7H), 1.50-1.00 (m,16H), 0.88 (s, 9H), 0.80 (s, 3H), 0.05 (s, 6H).

Synthesis of II-A8b

To a solution of II-A7b (1.7 g, 4.0 mmol) in THE (20 mL) was added TBAF(3.13 g, 12 mmol). The mixture was stirred at 20° C. for 4 h. Themixture was diluted with EtOAc (150 mL) and washed with water (3×100mL), dried over Na₂SO₄, filtered and concentrated and the resultingmaterial was triturated with PE (50 mL) at 60° C. to give II-A8b (1.1 g,89%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ_(H) 3.91 (t, J=7.2 Hz, 1H), 3.80-3.60 (m, 2H),3.52 (dd, J=3.6, 7.6 Hz, 1H), 3.44 (dd, J=7.6, 12.0 Hz, 1H), 1.90-1.75(m, 3H), 1.75-1.60 (m, 6H), 1.50-1.050 (m, 15H), 0.78 (s, 3H);LC-ELSD/MS purity 99%, MS ESI calcd. for C₁₉H₃₁O₂ [M+H-H₂O]⁺ 291.2,found 291.3.

Synthesis of II-A9b

To a solution of II-A8b (1.28 g, 4.1 mmol) in DCM (30 mL) was added DMP(3.51 g, 8.3 mmol) at 25° C. and inner temperature was raised to 30° C.The mixture was stirred at 30° C. for 1 h. The mixture was washed with amixed solution of NaHCO₃ (100 mL, sat.) and Na₂S₂O₃ (100 mL, sat.)twice, dried over Na₂SO₄, filtered and concentrated in vacuum to giveII-A9b (1.2 g, 95%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ_(H), 9.70 (d, J=2.4 Hz, 1H), 4.04 (t, J=7.6Hz, 1H), 3.77 (s, 1H), 3.63 (dd, J=7.6, 12.0 Hz, 1H), 1.95-1.35 (m,15H), 1.35-1.20 (m, 7H), 1.20-1.05 (m, 1H), 0.88 (s, 3H).

Synthesis of II-A10b

To a solution of II-A9b (1.2 g, 3.9 mmol) in THE (30 mL) was added MeLi(24.4 mL, 1.6 M, 39 mmol) at −70° C. The mixture was stirred at −70° C.for 1 h and warmed to 0° C. and stirred for 10 min. The mixture wasquenched by water (50 mL) and extracted with EtOAc (100 mL). The organiclayer was separated, dried over Na₂SO₄, filtered and concentrated invacuum to give I-A10b (1.16 g, 92%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ_(H), 3.90-3.80 (m, 2H), 3.45-3.35 (m 1H),3.10-3.05 (m, 1H), 1.95-1.75 (m, 6H), 1.75-1.60 (m, 7H), 1.50-1.20 (m,14H), 0.91 (s, 3H).

Synthesis of II-A11b

To a solution of I-A10b (1.16 g, 3.6 mmol) in DCM (30 mL) was added DMP(3.04 g, 7.2 mmol) at 25° C. and inner temperature was raised to 30° C.The mixture was stirred at 30° C. for 1 h. The mixture was washed with amixed solution of NaHCO₃ (100 mL, sat.) and Na₂S₂O₃ (100 mL, sat.)twice, dried over Na₂SO₄, filtered, concentrated in vacuum and purifiedby flash column (10˜30% EtOAc in PE) to give I-A11b (570 mg, 50%, 24 mgdelivered) as a solid. The structure was confirmed by 2D NMR.

¹H NMR (400 MHz, CDCl₃) δ_(H) 3.79 (t, J=8.0 Hz, 1H), 3.88 (s, 1H), 3.60(dd, J=7.6, 11.6 Hz, 1H), 2.16 (s, 3H), 1.95-1.60 (m, 7H), 1.50-1.30 (m,7H), 1.30-1.10 (m, 8H), 0.90-0.80 (m, 1H), 0.76 (s, 3H); LC-ELSD/MSpurity 99%, MS ESI calcd. for C₂₀H₃₃O₃ [M+H]+ 321.2, found 321.2.

Example II-2: Synthesis of1-(2-((1S,3aS,3bR,5aR,7R,9aS,9bR,11aS)-7-hydroxy-7,11a-dimethylhexadecahydrophenanthro[1,2-c]furan-1-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile(II-A13b)

Synthesis of II-A12b

To a solution of II-A11b (150 mg, 0.47 mmol) in MeOH (3 mL) was addedHBr (18.9 mg, 0.1 mmol, 40% in water) and Br₂ (74.7 mg, 0.47 mmol) at25° C. The mixture was stirred at 25° C. for 3 hrs. The mixture waspoured into NaHCO₃ (10 mL, saturated), extracted with EtOAc (2×10 mL).The organic layer was separated, dried over Na₂SO₄, filtered andconcentrated in vacuum to give II-A12b (200 mg) as a solid.

Synthesis of II-A13b

To a solution of II-A12b (200 mg, 0.5 mmol) in acetone (3 mL) was added4-cyanopyrazole (69.9 mg, 0.8 mmol) and K₂CO3 (345 mg, 2.5 mmol). Themixture was stirred at 25° C. for 16 hrs. To the mixture was added water(20 mL) and the mixture was extracted with EtOAc (2×20 mL). The organiclayer was separated, concentrated and purified by flash column (25˜60%EtOAc in PE) to give II-A13b (100 mg). The material (100 mg) waspurified by HPLC separation to give II-A13b (4 mg, 2%) as a solid.

¹H NMR (400 MHz, CDCl₃) δ_(H) 7.85-7.80 (m, 2H), 5.38-5.09 (m, 2H), 4.05(t, J=7.6 Hz, 1H), 3.98 (s, 1H), 3.67 (dd, J=8.0, 12.0 Hz, 1H),1.95-1.66 (m, 7H), 1.52-1.37 (m, 8H), 1.35-1.19 (m, 7H), 1.17-1.00 (m,1H), 0.86 (s, 3H); LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₄H₃₄N₃O₃[M+H]⁺ 412.2, found 412.2.

Example 3: Synthesis of1-((1R,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethylhexadecahydro-2H-naphtho[1,2-h]isochromen-1-yl)ethan-1-one(II-B12)

Synthesis of II-B2

To a solution of i-Pr₂NH (13.8 g, 137 mmol) in THF (100 mL) was addedBuLi (54.8 mL, 2.5 M, 137 mmol) at −70° C. which was warmed to 0° C. andstirred for 10 min. To the freshly prepared LDA solution at −70° C. wasadded a solution of II-B1 (10 g, 34.4 mmol, reported in patent‘WO2014/169833, 2014, A1’) in THE (100 mL). After stirring at −70° C.for 1 h, the mixture was added TMSCl (11.1 g, 103 mmol) in THF. Afterstirring at −70° C. for 1 h and then at 0° C. for 15 min, the mixturewas quenched with NH₄Cl (100 mL, sat.) and extracted with EtOAc (200mL). The organic layer was separated, dried over Na₂SO₄, filtered andconcentrated in vacuum to give II-B2 (16.2 g) as an oil. ¹H NMR (400MHz, CDCl₃) δ_(H) 4.52-4.45 (m, 1H), 2.04-1.95 (m, 1H), 1.90-1.55 (m,7H), 1.50-1.35 (m, 6H), 1.35-1.20 (m, 7H), 1.20-1.00 (m, 4H), 0.82 (s,3H), 0.19 (s, 9H).

Synthesis of II-B3

To a solution of II-B2 (16.2 g, 44.6 mmol) in DCM (240 mL) and MeCN (80mL) was added Pd(OAc)₂ (10 g, 44.6 mmol). After stirring at 15° C. for16 h, the reaction mixture was filtered through a pad of celite andwashed with DCM (100 mL). The combined organic filtrate was washed witha mixed solution of Na₂EDTA (15 g) and Na₂CO₃ (10 g) in water (200 mL),dried over Na₂SO₄, filtered, concentrated in vacuum and purified byflash column (15-50% EtOAc in PE) to give II-B3 (9 g, 90% yield for 2steps) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.52 (dd, J=0.8, 6.0Hz, 1H), 6.02 (dd, J=3.2, 6.0 Hz, 1H), 2.43-2.41 (m, 1H), 1.96-1.61 (m,8H), 1.59-1.26 (m, 13H), 1.26-1.19 (m, 1H), 1.07 (s, 3H). LC-ELSD/MSpurity 99%, MS ESI calcd. for C₁₉H₂₇O [M+H-H₂O]⁺ 271.2, found 271.2.

Synthesis of II-B4

To a solution of II-B4 (7.5 g, 26.0 mmol) in MeOH (150 mL) and THE (30mL) was added CeCl₃.7H₂O (10.6 g, 28.6 mmol) and Me₂S (400 mg, 6.4mmol). After stirring for 1 h at 15° C. NaBH₄ (983 mg, 26.0 mmol) wasadded in small portions maintaining a temperature at −5° C. Afterstirring for 10 min at 0° C., the mixture was quenched with NH₄Cl (50mL, sat.), diluted with water (300 mL) and filtered. The solid waswashed with water (3×50 mL), dried in vacuum to give II-B4 (7.3 g, 97%)The regiochemical assignment of H17 was by NOE. ¹H NMR (400 MHz, CDCl₃)δ_(H) 5.91 (d, J=5.6 Hz, 1H), 5.72-5.56 (m, 1H), 4.38-4.26 (m, 1H),1.92-1.80 (m, 5H), 1.74-1.60 (m, 3H), 1.55-1.28 (m, 13H), 1.25-1.07 (m,3H), 0.82 (s, 3H); LC-ELSD/MS purity 99%, MS ESI calcd. for C₁₉H₂₈[M+H-2H₂O]⁺ 255.2, found 255.3.

Synthesis of II-B5

To a suspension of III-B4 (4.5 g, 15.4 mmol) in THE (50 mL) at 20° C.was added NaH (2.45 g, 60%, 61.6 mmol) and BnBr (10.5 g, 61.6 mmol) andHMPA (2.75 g, 15.4 mmol). After stirring at 40° C. for 16 h, the mixturewas quenched with NH₄Cl solution (50 mL, sat.) and extracted withPE/EtOAc (10:1, 300 mL). The combined organic solution was dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography (0˜30% EtOAc in PE) to give II-B5 (5.4 g, 92%) as asolid. ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.45-7.30 (m, 5H), 5.95-5.85 (m,1H), 5.75-5.65 (m, 1H), 4.70-7.50 (m, 2H), 4.15-4.10 (m, 1H), 2.00-1.75(m, 8H), 1.75-1.50 (m, 6H), 1.50-1.30 (m, 4H), 1.27 (s, 3H), 1.20-1.05(m, 2H), 0.83 (s, 3H).

Synthesis of II-B6

To a solution of II-B5 (4.99 g, 13.1 mmol) in DCM (50 mL) and MeOH (50mL) was added NaHCO₃ (4.99 g, 59.4 mmol). To the mixture was passedozone (1 atm) at −70° C. until the mixture was turned blue (ca. 10 min)followed by O₂ for an additional 5 mins until the solution turnedcolorless. To the mixture was added NaBH₄ (1.98 g, 52.4 mmol) at −70° C.in portions. After warming to 0° C. over 1 h, the mixture was quenchedwith NH₄Cl (100 mL, sat., aq.) and extracted with DCM (3×30 mL). Thecombined organic solution was dried over Na₂SO₄, filtered, concentratedin vacuum to give a lactol intermediate (4.4 g). To a solution of thelactol intermediate (4.4 g) in THE (20 mL) and i-PrOH (20 mL) was addedNaBH₄ (1.86 g, 49.4 mmol). After stirring at 70° C. for 16 h, themixture was quenched by NH₄Cl (30 mL, sat.) and concentrated to removemost organic solvent. The residue was extracted with EtOAc (2×30 mL).The combined organic layer was dried over Na₂SO₄, filtered andconcentrated and purified by flash column (25˜50% EtOAc in PE) to giveII-B6 (2.9 g, 53%) as an oil. ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.45-7.30(m, 5H), 4.80-4.65 (m, 2H), 3.95-3.80 (m, 2H), 3.70-3.60 (m, 2H),3.40-3.35 (m, 1H), 2.40-2.10 (br, 2H), 1.90-1.70 (m, 4H), 1.70-1.40 (m,8H), 1.40-1.35 (m, 4H), 1.35-1.20 (m, 4H), 1.20-1.00 (m, 3H), 0.95 (s,3H).

Synthesis of II-B7

To a solution of II-B6 (2.9 g, 6.96 mmol) in THE (45 mL) was added BuLi(3.06 mL, 2.5 M in hexane, 7.6 mmol) at 0° C. After stirring for 10 min,TsCl (1.45 g, 1.83 mmol) in THE (5 mL) was added at 0° C. After stirringfor 10 min, additional BuLi (3.06 mL, 2.5 M in hexane, 7.6 mmol) wasadded at 0° C. After stirring for 30 min, a 3^(rd) batch of BuLi (2 mL,2.5 M in hexane, 5.0 mmol) was added at 0° C. After stirring for 10 min,additional TsCl (1.0 g. 5.2 mmol) in THE (3 mL) was added at 0° C. Afteran additional 10 min, a final batch of BuLi (2 mL, 2.5 M in hexane, 5.0mmol) was added at 0° C. and stirred for 30 min. The mixture wasquenched by NH₄Cl (20 mL, sat.) and extracted with EtOAc (100 mL). Theorganic solution was separated, dried over Na₂SO₄, filtered,concentrated and triturated from EtOAc (15 mL) to give II-B7 (1.5 g,54%) as a solid. The stereochemical assignment of C₁₇a was confirmed byHMBC. ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.36-7.27 (m, 5H), 4.58 (d, J=12.0Hz, 1H), 4.50 (d, J=11.6 Hz, 1H), 3.78 (dd, J=4.8, 11.2 Hz, 1H), 3.72(dd, J=4.4, 11.6 Hz, 1H), 3.40 (t, J=10.8 Hz, 1H), 3.22 (t, J=11.6 Hz,1H), 3.14 (dd, J=4.8, 10.8 Hz, 1H), 2.05-2.00 (m, 1H), 1.90-1.85 (m,1H), 1.80-1.65 (m, 4H), 1.55-1.30 (m, 10H), 1.26 (s, 3H), 1.15-1.00 (m,4H), 0.97 (s, 3H).

Synthesis of II-B8

To a solution of II-B77 (1.9 g, 4.8 mmol) in THE (20 mL) was addedPd(OH)₂/C (dry, 10%, 1 g) under N₂. The suspension was degassed undervacuum and purged with H₂ for three times. The mixture was stirred underH₂ (45 psi) at 40° C. for 16 hours to give a black suspension. Themixture was filtered through a pad of celite and washed with THE (3×10mL). The filtrate was concentrated and was triturated from EtOAc (20 mL)to give II-B8 (1.1 g, 75%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)3.74 (dd, J=4.0, 11.2 Hz, 1H), 3.67 (dd, J=3.6, 9.2 Hz, 1H), 3.45-3.30(m, 2H), 3.22 (t, J=11.2 Hz, 1H), 2.00-1.85 (m, 2H), 1.80-1.70 (m, 3H),1.65-1.50 (m, 3H), 1.50-1.35 (m, 6H), 1.35-1.20 (m, 6H), 1.15-0.95 (m,4H), 0.93 (s, 3H); LC-ELSD/MS purity 99%, MS ESI calcd. for C₁₉H₂₉O[M+H-2H₂O]⁺ 273.2, found 273.2.

Synthesis of II-B9

To a solution of II-B8 (0.4 g, 1.3 mmol) in DCM (10 mL) was added DMP(1.09 g, 2.6 mmol) at 25° C. After stirring at 30° C. for 1 h, thereaction mixture was washed with a mixed solution of NaHCO₃ (50 mL,sat.) and Na₂S₂O₃ (50 mL, sat.) twice, dried over Na₂SO₄, filtered,concentrated and purified by flash column (10˜30% EtOAc in PE) to giveII-B9 (370 mg, 92%, impure) as an oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)4.12 (d, J=16.8 Hz, 1H), 4.03 (dd, J=6.8, 10.8 Hz, 1H), 3.97 (d, J=17.2Hz, 1H), 3.63 (t, J=11.2 Hz, 1H), 1.95-1.85 (m, 2H), 1.85-1.70 (m, 4H),1.70-1.60 (m, 2H), 1.55-1.50 (m, 1H), 1.45-1.25 (m, 11H), 1.25-0.95 (m,6H); LC-ELSD/MS purity 99%, MS ESI calcd. for C₁₉H₂₉O₂ [M+H-H₂O]⁺ 289.2,found 289.1.

Synthesis of II-B10

To a mixture of EtPPh₃Br (10 g, 27 mmol) in THE (40 mL) was added t-BuOK(3.02 g, 27 mmol) under N₂. After stirring at 50° C. for 30 min, asolution of II-B9 (1.38 g, 4.5 mmol) in THF (10 mL) was added at 50° C.After stirring at 60° C. for 16 h, traction mixture was quenched with10% NH₄Cl aqueous (30 mL) at 15° C. and extracted with EtOAc (50 mL).The organic solution was concentrated under vacuum and purified by flashcolumn (10-20% EtOAc in PE) to give II-B10 (1.38 g, 96%) as a solid. ¹HNMR (400 MHz, CDCl₃) δ_(H) 5.30-5.20 (m, 1H), 4.10-4.00 (m, 1H),3.95-3.80 (m, 2H), 3.40-3.30 (m, 1H), 2.30-2.20 (m, 1H), 1.90-1.80 (m,1H), 1.80-1.65 (m, 4H), 1.65-1.50 (m, 3H), 1.50-1.30 (m, 8H), 1.30-1.20(m, 6H), 1.17 (s, 3H), 1.10-1.00 (m, 3H).

Synthesis of II-B11

To a solution of II-B10 (1.18 g, 3.7 mmol) in TH (20 mL) was addedBH₃.Me₂S (1.84 mL, 10 M, 18.5 mmol). After stirring at 25° C. for 16 h,EtOH (3.4 g, 74 mmol) was added dropwise followed by NaOH (7.39 mL, 5 M,37 mmol) and H₂O₂(3.69 mL, 10 M, 37 mmol). After stirring at 50° C. for1 h, the mixture was quenched by Na₂SO₃ (60 mL, 10%) and extracted withEtOAc (80 mL). The organic layer was separated, dried with Na₂SO₄,filtered and concentrated to give II-B11 (1.6 g) as a solid.

Synthesis of II-B12

To a solution of II-B11 (1.6 g, 4.7 mmol) in DCM (30 mL) was added DMP(4.02 g, 9.5 mmol) at 25° C. After stirring at 30° C. for 1 h, themixture was washed with a mixed solution of NaHCO₃ (100 mL, sat.) andNa₂S₂O₃ (100 mL, sat.) twice, dried over Na₂SO₄, filtered, concentratedand purified by flash column (20˜40% EtOAc in PE) to give II-B12 (0.99g, 80% yield for 2 steps) as an oil. A batch of II-B12 (150 mg) wasfurther purified by prep-HPLC (Instrument: AA; Column: Xbridge 150*30mm*10 μm; Condition: water (10 mM NH₄HCO₃)-ACN; Begin B: 48; End B: 68;Gradient Time (min): 7; 100% B Hold Time (min): 0; FlowRate (mL/min):25) and lyophilized to give II-B12 (62 mg) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H) 3.81 (dd, J=4.0, 11.2 Hz, 1H), 3.77 (t, J=11.6 Hz, 1H),3.67 (dd, J=4.0, 11.6 Hz, 1H), 3.24 (t, J=11.6 Hz, 1H), 2.68 (dd, J=4.0,11.2 Hz, 1H), 2.17 (s, 3H), 1.89-1.67 (m, 5H), 1.55-1.23 (m, 15H),1.14-0.98 (m, 6H); LC-ELSD/MS purity 99%, MS ESI calcd. for C₂₁H₃₃O₂[M+H-H₂O]⁺ 317.2, found 317.2.

Example 4: Synthesis of1-(2-((1R,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethylhexadecahydro-2H-naphtho[1,2-h]isochromen-1-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile(II-B14)

Synthesis of II-B13

To a solution of II-B12 (220 mg, 0.65 mmol) in MeOH (2 mL) was added HBr(26.5 mg, 0.13 mmol, 40% aq.) and Br₂ (105 mg, 0.65 mmol) at 25° C.After stirring at 25° C. for 3 h, the mixture was quenched by NaHCO₃ (2mL, saturated) and extracted with EtOAc (2×5 mL). The combined organicsolution was dried over Na₂SO₄, filtered and concentrated in vacuum togive II-B13 (220 mg, 81% yield) as a solid.

Synthesis of II-B14

To a solution of II-B13 (220 mg, 0.53 mmol) in acetone (3 mL) was added4-cyano-pyrazole (197 mg, 2.1 mmol) and K₂CO₃ (292 mg, 2.1 mmol). Afterstirring at 25° C. for 16 h, the reaction mixture was diluted with water(10 mL) and extracted with EtOAc (2×10 mL). The combined organicsolution was concentrated and purified by prep-HPLC (Instrument: BF;Column: Xtimate C18 150*25 mm*5 μm; Condition: water (0.225% FA)-ACN;Begin B: 50; End B: 70; Gradient Time (min): 7.5; 100% B Hold Time(min): 2; FlowRate (mL/min): 30), lyophilized and re-crystallized fromMeCN/H₂O (20 mL, 1:1) to give II-B14 (84 mg, 37%) as a solid. ¹H NMR(400 MHz, CDCl₃) δ_(H), 7.84-7.78 (m, 2H), 5.07 (d, J=18.0 Hz, 1H), 4.95(d, J=18.6 Hz, 1H), 3.88-3.77 (m, 2H), 3.71 (dd, J=3.6, 11.6 Hz, 1H),3.27 (t, J=11.6 Hz, 1H), 2.72 (dd, J=3.6, 11.2 Hz, 1H), 1.89-1.69 (m,5H), 1.55-1.24 (m, 15H), 1.16-0.99 (m, 6H); LC-ELSD/MS purity 99%, MSESI calcd. for C₂₅H₃₄N₃O₂ [M+H-H₂O]⁺ 408.3, found 408.2.

Biological Data

Steroid Inhibition of TBPS Binding

[³⁵S]-t-Butylbicyclophosphorothionate (TBPS) binding assays using ratbrain cortical 25 membranes in the presence of 5 mM GABA has beendescribed (Gee et al, J. Pharmacol. Exp. Ther. 1987, 241, 346-353;Hawkinson et al, Mol. Pharmacol. 1994, 46, 977-985; Lewin, A. H et al.,Mol. Pharmacol. 1989, 35, 189-194).

Briefly, cortices are rapidly removed following decapitation of carbondioxide-anesthetized Sprague-Dawley rats (200-250 g). The cortices arehomogenized in 10 volumes of ice-cold 0.32 M sucrose using aglass/teflon homogenizer and centrifuged at 1500×g for 10 min at 4° C.The resultant supernatants are centrifuged at 10,000×g for 20 min at 4°C. to obtain the P2 pellets. The P2 pellets are resuspended in 200 mMNaC/50 mM Na—K phosphate pH 7.4 buffer and centrifuged at 10,000×g for10 min at 4° C. This washing procedure is repeated twice and the pelletsare resuspended in 10 volumes of buffer. Aliquots (100 mL) of themembrane suspensions are incubated with 3 nM [³⁵S]-TBPS and 5 mLaliquots of test drug dissolved in dimethyl sulfoxide (DMSO) (final0.5%) in the presence of 5 mM GABA. The incubation is brought to a finalvolume of 1.0 mL with buffer. Nonspecific binding is determined in thepresence of 2 mM unlabeled TBPS and ranged from 15 to 25%. Following a90 min incubation at room temp, the assays are terminated by filtrationthrough glass fiber filters (Schleicher and Schuell No. 32) using a cellharvester (Brandel) and rinsed three times with ice-cold buffer. Filterbound radioactivity is measured by liquid scintillation spectrometry.Non-linear curve fitting of the overall data for each drug averaged foreach concentration is done using Prism (GraphPad). The data are fit to apartial instead of a full inhibition model if the sum of squares issignificantly lower by F-test. Similarly, the data are fit to a twocomponent instead of a one component inhibition model if the sum ofsquares is significantly lower by F-test. The concentration of testcompound producing 50% inhibition (IC₅₀) of specific binding and themaximal extent of inhibition (I_(max)) are determined for the individualexperiments with the same model used for the overall data and then themeans±SEM.s of the individual experiments are calculated. Picrotoxinserves as the positive control for these studies as it has beendemonstrated to robustly inhibit TBPS binding.

Various compounds are or can be screened to determine their potential asmodulators of [35S]-TBPS binding in vitro. These assays are or can beperformed in accordance with the above.

Example I-3

In Table I-1 below, A indicates a TBPS IC₅₀ (μM)<0.1 μM, B indicates aTBPS IC₅₀ (μM) of 0.1 μM to <1 μM, C indicates a TBPS IC₅₀ (μM) of 1 μMto <10 μM, D means≥10 μM.

TABLE I-1 Example Compound ID STRUCURE IC₅₀ (μM) I-1 I-A15

C I-2 I-A17

C

Example II-9

In Table II-2 below, A indicates a TBPS IC50 (μM)<0.1 μM, B indicates aTBPS IC50 (μM) of 0.1 μM to <1 μM, C indicates a TBPS IC50 (μM) of 1 μMto <10 μM, D means≥10 μM.

TABLE II-2 Example Compound ID Structure IC₅₀ (μM) II-1 II-A11b

D II-2 II-A13b

C II-3 II-B12

B II-4 II-B14

B

Equivalents and Scope

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

The invention claimed is:
 1. A compound of Formula (II-IIwa), (II-IIwb),or (II-IIwc)

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, or3; p is 0, 1, or 2; and each R₃₂ is independently halogen, C₁₋₆ alkyl,hydroxyl, or cyano.
 2. The compound or pharmaceutically acceptable saltof claim 1, wherein m is 1, and p is
 1. 3. A compound selected from

or a pharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition comprising a compound or pharmaceutically acceptable salt ofclaim 1 or claim 3, and a pharmaceutically acceptable excipient.
 5. Amethod for treating a CNS-related disorder in a subject in need thereof,the method comprising administering to the subject a therapeuticallyeffective amount of a compound, or pharmaceutically acceptable saltthereof, of claim 1 or claim 3, wherein the CNS-related disorder is asleep disorder, a mood disorder, a schizophrenia spectrum disorder, aconvulsive disorder, a disorder of memory and/or cognition, a movementdisorder, a personality disorder, autism spectrum disorder, pain,traumatic brain injury, a vascular disease, tinnitus, or statusepilepticus.
 6. The method of claim 5, wherein the CNS-related disorderis a mood disorder, and wherein the mood disorder is depression.
 7. Themethod of claim 6, wherein the depression is postpartum depression or amajor depressive disorder.
 8. The method of claim 7, wherein the majordepressive disorder is a moderate major depressive disorder or a severemajor depressive disorder.
 9. The method of claim 5, wherein theCNS-related disorder is a movement disorder, and wherein the movementdisorder is seizure or tremor.
 10. The method of claim 9, wherein thetremor is essential tremor.
 11. The compound or pharmaceuticallyacceptable salt of claim 1, wherein the compound of Formula (II-IIwa),(II-IIwb), or (II-IIwc) is a compound of Formula (II-IIwa):

or a pharmaceutically acceptable salt thereof.
 12. The compound orpharmaceutically acceptable salt of claim 1, wherein the compound ofFormula (II-IIwa), (II-IIwb), or (II-IIwc) is a compound of Formula(II-IIwb):

or a pharmaceutically acceptable salt thereof.
 13. The compound orpharmaceutically acceptable salt of claim 1, wherein the compound ofFormula (II-IIwa), (II-IIwb), or (II-IIwc) is a compound of Formula(II-IIwc):

or a pharmaceutically acceptable salt thereof.